Metabolic and functional reprogramming of myeloid-derived suppressor cells and their therapeutic control in glioblastoma

Glioblastoma, also known as glioblastoma multiforme, is the most common and deadliest form of high-grade malignant brain tumors with limited available treatments. Within the glioblastoma tumor microenvironment (TME), tumor cells, stromal cells, and infiltrating immune cells continuously interact and exchange signals through various secreted factors including cytokines, chemokines, growth factors, and metabolites. Simultaneously, they dynamically reprogram their metabolism according to environmental energy demands such as hypoxia and neo-vascularization. Such metabolic reprogramming can determine fates and functions of tumor cells as well as immune cells. Ultimately, glioma cells in the TME transform immune cells to suppress anti-tumor immune cells such as T, natural killer (NK) cells, and dendritic cells (DC), and evade immune surveillance, and even to promote angiogenesis and tumor metastasis. Glioma-associated microglia/macrophages (GAMM) and myeloid-derived suppressor cells (MDSC) are most abundantly recruited and expanded myeloid lineage cells in glioblastoma TME and mainly lead to immunosuppression. In this review, of myeloid cells we will focus on MDSC as an important driver to induce immunosuppression in glioblastoma. Here, we review current literature on immunosuppressive functions and metabolic reprogramming of MDSCs in glioblastoma and discuss their metabolic pathways as potential therapeutic targets to improve current incurable glioblastoma treatment

Forkhead factor, FOXO3a, induces apoptosis of endothelial cells through activation of matrix metalloproteinases

BACKGROUND: The forkhead factor, FOXO3a, is known to induce apoptosis in endothelial cells (ECs). However, its effects on extracellular matrices (ECM), which are important in EC survival, remained unknown. Here, we evaluated the role of FOXO3a on EC-ECM interaction. METHODS AND RESULTS: Constitutively active FOXO3a was transduced to human umbilical vein endothelial cells by adenoviral vector (Ad-TM-FOXO3a). Ad-TM-FOXO3a transfection led to dehiscence of ECs from fibronectin-coated plates, resulting in anoikis, which was significantly reversed by matrix metalloproteinase (MMP) inhibitor, GM6001. FOXO3a increased the expression of MMP-3 (stromelysin-1) but decreased the expression of tissue inhibitors of metalloproteinases-1 (TIMP-1), which was associated with increased MMP enzymatic activity in zymography. Pathophysiologic conditions such as serum starvation or heat shock also induced activation of endogenous FOXO3a, leading to activation of MMP-3 and apoptosis, which was reversed by GM6001. Delivery of Ad-TM-FOXO3a to the intraluminal surface in vivo led to EC denudation, disrupted vascular integrity, and impaired endothelium-dependent vasorelaxation. CONCLUSIONS: Activation of MMPs and possible ECM disruption represent novel mechanisms of FOXO3a-mediated apoptosis in ECs

Integrin-linked kinase, a hypoxia-responsive molecule, controls postnatal vasculogenesis by recruitment of endothelial progenitor cells to ischemic tissue

BACKGROUND: Recruitment and adhesion of endothelial progenitor cells (EPCs) to hypoxic endothelial cells (ECs) is essential for vasculogenesis in ischemic tissue; little is known, however, about the key signals or intracellular signaling pathways involved in orchestrating the expression of adhesion molecules by ECs in response to hypoxia and how this is related to the recruitment of EPCs to the ischemic tissue. Here, we report that endogenous integrin-linked kinase (ILK) is a novel molecule that responds to hypoxia in ECs that regulates the expression of stromal cell-derived factor-1 (SDF-1) and intercellular adhesion molecule-1 (ICAM-1) through nuclear factor-kappaB and hypoxia-inducible factor-1alpha and induces recruitment of EPCs to ischemic areas. METHODS AND RESULTS: Under hypoxia, both the endogenous amount and kinase activity of ILK were time-dependently upregulated in ECs, which was associated with increased ICAM-1 and SDF-1. This upregulation of ILK was mediated by stabilization of ILK by heat shock protein 90. ILK overexpression in normoxic ECs resulted in ICAM-1 and SDF-1 upregulation through dual control by nuclear factor-kappaB and hypoxia-inducible factor-1alpha. Blockade of ILK in hypoxic ECs significantly abrogated the expression of both molecules, which led to decreased EPC incorporation into ECs. A hindlimb ischemia model showed that ILK blockade significantly reduced EPC homing to ischemic limb and consequently led to poor neovascularization. Overexpression of ILK in the Matrigel plug significantly improved neovascularization in vivo, whereas the blockade of ILK resulted in the opposite effect. CONCLUSIONS: Endogenous ILK is a novel and physiological upstream responder of numerous intracellular molecules involved in hypoxic stress in ECs and may control the recruitment of EPCs to ischemic tissue

The photovoltaic effect of the p-n heterojunction organic photovoltaic device using a nano template method

Characteristics of ITO/polypyrrole (PPy) nano fibers/poly(3-hexylthiophene)/Al photovoltaic devices prepared by nano template method were studied. PPy nano fibers on ITO glass were formed through nano pores of polymer membrane template using home made special sample holder by electrochemical polymerization in an electrolyte solution of pyrrole and lithium perchlorate as a dopant in acetonitrile. Ordered structure with enhanced interfacial area formed by nano template method enable to fabricate polymeric photovoltaic device with improved photo-conversion efficiency. This nano fiber structures film possesses increased interfacial area, large charge separation area (photoactive zone) and secured charge transportation route. The effect of altering energy levels of PPy by changing doped state was also studied. Device made with nano fiber structure showed enhanced photovoltaic effect than that of overlayed film device

The Impact of HER2-Low Expression on Oncologic Outcomes in Hormone Receptor-Positive Breast Cancer

Breast cancer is a prevalent malignancy with increasing incidence, particularly in Asian countries. Classification based on estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status is pivotal in determining treatment. Recent advances have challenged the traditional dichotomy in HER2 classification, prompting investigation into the HER2-low subtype’s characteristics and outcomes. This retrospective study analyzed 10,186 non-metastatic hormone receptor (HR)-positive, HER2-negative breast cancer cases treated from 2008 to 2020. Data encompassed clinical, pathological, and treatment information. Oncologic outcomes included disease-free survival (DFS), overall survival (OS), and breast cancer-specific survival (BCSS). In total, 56.5% were HER2-low cases. Differences in patient characteristics were noted, with more BRCA1/2 mutations and higher mastectomy rates in the HER2-low group (p = 0.002, p p p = 0.012, p = 0.013, and p = 0.013, respectively). Notably, the prognosis differed between premenopausal and postmenopausal subgroups, with BCSS benefitting premenopausal patients (p = 0.047) and DFS and OS benefitting postmenopausal patients in the HER2-low group (p = 0.004, p = 0.009, respectively). Multivariate analysis confirmed HER2 status as an independent predictor of these outcomes (p = 0.010, p = 0.008, and p = 0.014, respectively). This extensive single-center study elucidates the favorable prognosis associated with HER2-low status in HR-positive breast cancer. However, this effect differs among premenopausal and postmenopausal patients, necessitating further research into the underlying tumor biology

Recurrence of hepatitis B is associated with cumulative corticosteroid dose and chemotherapy against hepatocellular carcinoma recurrence after liver transplantation

The incidence of hepatitis B (HB) recurrence after a liver transplantation has been reduced by prophylaxis with hepatitis B immunoglobulin (HBIG) and lamivudine. However, the long-term incidence of recurrence is <10%, and the factors associated with HB recurrence are unclear. This study analyzed the factors associated with HB recurrence in 203 recipients who underwent liver transplantation for HB in 3 major centers in Korea over 4 years. Eighty-five patients (41.9%) had a hepatocellular carcinoma (HCC). Preoperative active virus replicators with the HBeAg(+) (46.8%) and/or hepatitis B virus DNA(+) (39.4%) were observed in 136 patients (67.0%). The HB prophylaxis consisted of either HBIG monotherapy (n = 95, HBIG group) or combination therapy with lamivudine (n = 108, combination group). HB recurrence was defined as the appearance of the HBsAg. The follow-up period was 28.3 +/- 13.1 months (mean +/- SD). HB recurred in 21 patients (10.3%) after transplantation. The time from transplantation to recurrence was 16.3 +/- 9.4 months. Pre-LT DNA positivity was more prevalent in HBIG group (55.8%) than in the combination group (39.8%) (P = 0.015). However, the incidence of HB recurrence was similar in the HBIG (6.3%) and combination group (13.8%), as well as between the active replicators (12.5%) and nonreplicators (4.1%) (P < 0.05). There was a far higher incidence of HB recurrence in patients receiving corticosteroid pulse therapy (21.0% vs. 7.9%), patients who experienced HCC recurrence (31.3% vs. 8.6%), and patients receiving chemotherapy to prevent HCC recurrence (25.0% vs. 4.4%) (P < 0.05). The cumulative corticosteroid dose was higher in patients who experienced recurrence of HB (P = 0.002). Multivariable analysis confirmed the effect of the cumulative corticosteroid dose and chemotherapy to be risk factors. Liver transplantation for HB is safe, with low recurrence rates if adequate prophylaxis is used. However, the cumulative corticosteroid dose and the chemotherapy used for HCC were risk factors for HB recurrence, so careful monitoring for HB recurrence is needed in these patients