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Proceedings of the National Academy of... Jul 2023Effects of micronutrients on brain connectivity are incompletely understood. Analyzing human milk samples across global populations, we identified the carbocyclic sugar...
Effects of micronutrients on brain connectivity are incompletely understood. Analyzing human milk samples across global populations, we identified the carbocyclic sugar -inositol as a component that promotes brain development. We determined that it is most abundant in human milk during early lactation when neuronal connections rapidly form in the infant brain. -inositol promoted synapse abundance in human excitatory neurons as well as cultured rat neurons and acted in a dose-dependent manner. Mechanistically, -inositol enhanced the ability of neurons to respond to transsynaptic interactions that induce synapses. Effects of -inositol in the developing brain were tested in mice, and its dietary supplementation enlarged excitatory postsynaptic sites in the maturing cortex. Utilizing an organotypic slice culture system, we additionally determined that -inositol is bioactive in mature brain tissue, and treatment of organotypic slices with this carbocyclic sugar increased the number and size of postsynaptic specializations and excitatory synapse density. This study advances our understanding of the impact of human milk on the infant brain and identifies -inositol as a breast milk component that promotes the formation of neuronal connections.
Topics: Female; Infant; Humans; Animals; Mice; Rats; Milk, Human; Breast Feeding; Neurons; Inositol; Sugars
PubMed: 37433002
DOI: 10.1073/pnas.2221413120 -
Science Advances Jul 2023The progression of noninvasive ductal carcinoma in situ to invasive ductal carcinoma for patients with breast cancer results in a significantly poorer prognosis and is...
The progression of noninvasive ductal carcinoma in situ to invasive ductal carcinoma for patients with breast cancer results in a significantly poorer prognosis and is the precursor to metastatic disease. In this work, we have identified insulin-like growth factor-binding protein 2 (IGFBP2) as a potent adipocrine factor secreted by healthy breast adipocytes that acts as a barrier against invasive progression. In line with this role, adipocytes differentiated from patient-derived stromal cells were found to secrete IGFBP2, which significantly inhibited breast cancer invasion. This occurred through binding and sequestration of cancer-derived IGF-II. Moreover, depletion of IGF-II in invading cancer cells using small interfering RNAs or an IGF-II-neutralizing antibody ablated breast cancer invasion, highlighting the importance of IGF-II autocrine signaling for breast cancer invasive progression. Given the abundance of adipocytes in the healthy breast, this work exposes the important role they play in suppressing cancer progression and may help expound upon the link between increased mammary density and poorer prognosis.
Topics: Female; Humans; Adipocytes; Antibodies, Neutralizing; Breast; Breast Neoplasms; Insulin-Like Growth Factor II
PubMed: 37436978
DOI: 10.1126/sciadv.adg1840 -
Journal of Menopausal Medicine Dec 2023Tibolone, a selective tissue estrogenic activity regulator, is a synthetic steroid with distinct pharmacological and clinical characteristics in contrast to conventional... (Review)
Review
Tibolone, a selective tissue estrogenic activity regulator, is a synthetic steroid with distinct pharmacological and clinical characteristics in contrast to conventional menopausal hormone therapy. Tibolone induces estrogenic activity in the brain, vagina, and bone but remains inactive in the endometrium and breast. In particular, several studies have investigated whether tibolone usage increases the risk of breast cancer. This study aims to determine the effects of tibolone on the breast by focusing on the relation between tibolone use and breast cancer. Our investigation emphasizes recent studies, particularly those based on Asian populations.
PubMed: 38230592
DOI: 10.6118/jmm.23032 -
Neurology Jul 2023Ischemic stroke (IS), 1 of the 2 main subtypes of stroke, occurs because of brain ischemia caused by thrombosis of a cerebral blood vessel. IS is one of the most...
BACKGROUND AND OBJECTIVES
Ischemic stroke (IS), 1 of the 2 main subtypes of stroke, occurs because of brain ischemia caused by thrombosis of a cerebral blood vessel. IS is one of the most important neurovascular causes of death and disability. It is affected by many risk factors, such as smoking and a high body mass index (BMI), which are also critical in the preventive control of other cardiovascular and cerebrovascular diseases. However, there are still few systematic analyses of the current and predicted disease burden and the attributable risk factors of IS.
METHODS
Based on the Global Burden of Disease 2019 database, we used age-standardized mortality rate and disability-adjusted life year to systematically present the geographical distribution and trends of IS disease burden worldwide from 1990 to 2019 by calculating the estimated annual percentage change and to analyze and predict the death number of IS accounted by 7 major risk factors for 2020-2030.
RESULTS
Between 1990 and 2019, the global number of IS deaths increased from 2.04 million to 3.29 million and is expected to increase further to 4.90 million by 2030. The downward trend was more pronounced in women, young people, and high sociodemographic index (SDI) regions. At the same time, a study of attributable risk factors of IS found that 2 behavioral factors, smoking and diet in high sodium, and 5 metabolic factors, including high systolic blood pressure, high low-density lipoprotein cholesterol, kidney dysfunction, high fasting plasma glucose, and a high BMI, are major contributors to the increased disease burden of IS now and in the future.
DISCUSSION
Our study provides the first comprehensive summary for the past 30 years and the prediction of the global burden of IS and its attributable risk factors until 2030, providing detailed statistics for decision-making on the prevention and control of IS globally. An inadequate control of the 7 risk factors would lead to an increased disease burden of IS in young people, especially in low SDI regions. Our study identifies high-risk populations and helps public health professionals develop targeted preventive strategies to reduce the global disease burden of IS.
Topics: Humans; Female; Adolescent; Ischemic Stroke; Quality-Adjusted Life Years; Risk Factors; Risk Assessment; Smoking; Global Health
PubMed: 37197995
DOI: 10.1212/WNL.0000000000207387 -
Journal of Hematology & Oncology Aug 2023Recently, therapeutic antibodies against programmed cell death 1 (PD-1) and its ligand (PD-L1) have exerted potent anticancer effect in a variety of tumors. However,...
BACKGROUND
Recently, therapeutic antibodies against programmed cell death 1 (PD-1) and its ligand (PD-L1) have exerted potent anticancer effect in a variety of tumors. However, blocking the PD-1/PD-L1 axis alone is not sufficient to restore normal immune response. Other negative regulators of antitumor immunity, like TGF-β and VEGFA, are also involved in immune escape of tumor cells and induce immunotherapy resistance.
METHODS
We developed a novel anti-TGF-β/VEGF bispecific antibody Y332D based on the Nano-YBODY™ technology platform. The CCK-8, flow cytometry, SBE4 luciferase reporter assay, western blotting and transwell assays were used to measure the biological activities of the anti-TGF-β moiety. The NFAT luciferase reporter assay, luminescent cell viability assay and tube formation assay were used to measure the biological activities of the anti-VEGF moiety. The in vivo anticancer efficacy of Y332D alone or in combination with PD-1 blockade was evaluated in H22, EMT-6, 4T1, and AKT/Ras-driven murine hepatocellular carcinoma tumor models. Immunofluorescent staining, flow cytometry, RNA-seq and quantitative RT-PCR were adopted to analyze the alterations in the tumor microenvironment.
RESULTS
Y332D could maintain specific binding affinities for TGF-β and VEGFA. Y332D almost entirely counteracted the in vitro biological functions of TGF-β and VEGFA, including immunosuppression, activated TGF-β signaling, epithelial-mesenchymal transition (EMT), activated VEGF/VEGFR signaling, HUVEC proliferation and tube formation. The in vivo experiment data demonstrated that Y332D was more effective in inhibiting tumor growth and metastasis than anti-TGF-β and anti-VEGF monotherapies. In combination therapies, Y332D plus PD-1 blockade exhibited the most potent and durable anticancer effect. Mechanistically, Y332D plus PD-1 blockade upregulated the density and function of tumor-infiltrating lymphocytes and exerted reinvigorated antitumor immunity.
CONCLUSION
Y332D could simultaneously block TGF-β and VEGF signalings. In comparison with the monotherapies, Y332D combined with PD-1 blockade exerts superior antitumor effect through improving immune microenvironment.
Topics: Humans; Animals; Mice; B7-H1 Antigen; Programmed Cell Death 1 Receptor; Transforming Growth Factor beta; Antibodies, Bispecific; Carcinoma, Hepatocellular; Liver Neoplasms; Tumor Microenvironment; Cell Line, Tumor
PubMed: 37573354
DOI: 10.1186/s13045-023-01487-5 -
Canadian Family Physician Medecin de... Feb 2024
Topics: Humans; Female; Breast Density; Mammography; Early Detection of Cancer; Breast Neoplasms; Mass Screening
PubMed: 38383013
DOI: 10.46747/cfp.700282 -
Cureus Aug 2023Osteoporosis affects a significant number of postmenopausal women in the United States. Screening is performed using clinical assessments and bone mineral density scans... (Review)
Review
Osteoporosis affects a significant number of postmenopausal women in the United States. Screening is performed using clinical assessments and bone mineral density scans via dual x-ray absorptiometry. Oral therapy is indicated to prevent pathologic fractures in those deemed at increased risk following screening. Bisphosphonates including alendronate, ibandronate, and risedronate are currently first-line oral therapeutics in fracture prevention following the diagnosis of osteoporosis. Hormonal therapies include estrogen-containing therapies, selective estrogen receptor modulators, and other compounds that mimic the effects of estrogen such as tibolone. Lifestyle modifications such as supplementation and physical activity may also contribute to the prevention of osteoporosis and are used as adjuncts to therapy following diagnosis. These therapeutics are limited primarily by their adverse effects. Treatment regimens should be tailored based on significant risk factors demonstrated by patients, adverse effects, and clinical response to treatment. The most severe risk factors relevant to pharmacological selection involve hormone replacement therapies, where concern for venous thrombosis, coronary artery disease, breast, and uterine cancer exist. Bisphosphonates are most commonly associated with gastrointestinal discomfort which may be mitigated with proper administration. Although adverse effects exist, these medications have proven to be efficacious in the prevention of vertebral and non-vertebral fractures in post-menopausal women. Fracture risk should be weighed against the risk of adverse events associated with each of the regimens, with clinical judgment dictating the treatment approach centered around patient goals and experiences.
PubMed: 37664395
DOI: 10.7759/cureus.42870 -
Science Immunology Jun 2023Analyses of healthy tissue reveal signatures that identify resident memory CD8 T cells (T), which survey tissues without recirculating. The density of T phenotype cells...
Analyses of healthy tissue reveal signatures that identify resident memory CD8 T cells (T), which survey tissues without recirculating. The density of T phenotype cells within solid tumors correlates favorably with prognosis, suggesting that intratumoral residents control cancer. However, residence has not been directly tested, and intratumoral T phenotype cells could instead reflect aspects of the microenvironment that correlate with prognosis. Using a breast cancer model in mice, we found that conventional T markers do not inform the tumor residence of either bystander or tumor-specific cells, which exhibit further distinct phenotypes in the tumor microenvironment and healthy mammary tissue. Rather, tumor-specific, stem progenitor CD8 T cells migrate to tumors and become resident while acquiring select markers of exhaustion. These data indicate that tonic antigen stimulation and the tumor environment drive distinct programs of residence compared with healthy tissues and that tumor immunity is sustained by continued migration of tumor-specific stem cells.
Topics: Mice; Animals; CD8-Positive T-Lymphocytes; Immunologic Memory; Neoplasms; Antigens; Prognosis; Tumor Microenvironment
PubMed: 37267383
DOI: 10.1126/sciimmunol.add5976