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2021 ◽  
pp. jim-2021-002047
Author(s):  
Angélica Araceli Ramírez-Guerrero ◽  
Christian Octavio González-Villaseñor ◽  
Evelia Leal-Ugarte ◽  
Melva Gutiérrez-Angulo ◽  
Mario Ramírez-Flores ◽  
...  

Colorectal cancer (CRC) is the third most common cancer and one of the main causes of death around the world. Multiple lines of evidence have suggested the role of the corticotropin-releasing hormone (CRH) family in CRC induction, including the low expression of corticotropin-releasing hormone receptor 2 (CRHR2), which is an angiogenesis inhibitor and inflammatory modulator. Previous research suggests that CRHR2 expression in colonic intestinal cells can regulate migration, proliferation and apoptosis through the modulation of several pathways. The aim of this study was to analyze the association of the rs10250835, rs2267716 and rs2267717 variants of CRHR2 gene with CRC in the Mexican population in order to consider its predictive value in CRC. This cross-sectional study included a group of 187 unrelated patients with sporadic CRC and a control group of 191 healthy blood donors. DNA extraction from peripheral blood was carried out using the Miller method. Identification of the rs10250835 variant was performed using PCR-restriction fragment length polymorphism (RFLP) and the rs2267716 and rs2267717 variants using TaqMan allelic discrimination assay. The minor allele homozygous CC of the rs2267716 variant of CRHR2 showed significant difference between CRC and control group (p=0.025), as well as the GCA haplotype (p=0.007), corresponding to the rs10250835, rs2267716 and rs2267717 variants, respectively. Our results suggest that the rs2267716 variant and GCA haplotype of CRHR2 represent a risk factor for CRC development in Mexican patients.


2021 ◽  
Vol 12 ◽  
Author(s):  
Kang Liang ◽  
Rui Zhang ◽  
Haiyan Luo ◽  
Jinlong Zhang ◽  
Zhenyuan Tian ◽  
...  

The gram-negative facultative anaerobic bacteria Salmonella enterica serovar Typhimurium (hereafter S. Typhimurium) has always been considered as one candidate of anti-tumor agents or vectors for delivering drug molecules. In this study, we compared several widely studied S. Typhimurium strains in their anti-tumor properties aiming to screen out the best one for further optimization and use in cancer therapy. In terms of the motility, virulence and anti-tumor efficacy, the three strains 14028, SL1344, and UK-1 were similar and obviously better than LT-2, and UK-1 showed the best phenotypes among them. Therefore, the strain UK-1 (D) was selected for the following studies. Its auxotrophic mutant strain (D1) harboring ∆aroA and ∆purM mutations was further optimized through the modification of lipid A structure, generating a new strain named D2 with stronger immunostimulatory activity. Finally, the ∆asd derivative of D2 was utilized as one live vector to deliver anti-tumor molecules including the angiogenesis inhibitor endostatin and apoptosis inducer TRAIL and the therapeutic and toxic-side effects were evaluated in mouse models of colon carcinoma and melanoma. After intraperitoneal infection, engineered Salmonella bacteria equipped with endostatin and/or TRAIL significantly suppressed the tumor growth and prolonged survival of tumor-bearing mice compared to PBS or bacteria carrying the empty plasmid. Consistently, immunohistochemical studies confirmed the colonization of Salmonella bacteria and the expression of anti-tumor molecules inside tumor tissue, which were accompanied by the increase of cell apoptosis and suppression of tumor angiogenesis. These results demonstrated that the beneficial anti-tumor efficacy of attenuated S. Typhimurium bacteria could be improved through delivery of drug molecules with powerful anti-tumor activities.


2021 ◽  
Vol 28 (6) ◽  
pp. 5266-5277
Author(s):  
Michalis Liontos ◽  
Eleni Timotheadou ◽  
Emmanuel I. Papadopoulos ◽  
Zafeiris Zafeiriou ◽  
Dimitra Ioanna Lampropoulou ◽  
...  

New treatment modalities have been recently introduced in the management of ovarian cancer (OC). Herein, we sought to investigate their implementation in routine clinical practice and examine the real-world management of OC in Greece. EpOCa was a non-interventional, multicenter, retrospective study in patients with advanced epithelial OC. The primary outcome was to estimate the proportions of the different treatment regimens used per line of therapy, while progression-free survival (PFS) and overall survival (OS) were the key secondary endpoints. A total of 154 patients were enrolled in the study, among whom, 40% were tested for BRCA mutations and 30% were found to be positive. Nearly 90% of patients underwent debulking surgery at diagnosis, with few operations being also recorded upon relapse. Platinum-based chemotherapy (CT) was predominantly used in the first line with half of patients also receiving angiogenesis inhibitor (AI), while non-platinum-based CT was preferred in later lines. The median PFS was 18.2 and 8.8 months in the first- and second-line setting, respectively, whereas the median OS was approximately 50 months. Our study adds to the available, but limited, real world data on the management of ovarian cancer providing evidence regarding the applied treatment strategies and outcomes of patients in Greece.


2021 ◽  
Vol 15 ◽  
Author(s):  
Sahlia Joseph-Pauline ◽  
Nathan Morrison ◽  
Michael Braccia ◽  
Alana Payne ◽  
Lindsay Gugerty ◽  
...  

Focal brain injury in the form of a needlestick (NS) results in cell death and induces a self-protective response flanking the lesion. Myo/Nog cells are identified by their expression of bone morphogenetic protein inhibitor Noggin, brain-specific angiogenesis inhibitor 1 (BAI1) and the skeletal muscle specific transcription factor MyoD. Myo/Nog cells limit cell death in two forms of retinopathy. In this study, we examined the acute response of Myo/Nog cells to a NS lesion that extended from the rat posterior parietal cortex to the hippocampus. Myo/Nog cells were identified with antibodies to Noggin and BAI1. These cells were the primary source of both molecules in the uninjured and injured brain. One day after the NS, the normally small population of Myo/Nog cells expanded approximately eightfold within a 1 mm area surrounding the lesion. Myo/Nog cells were reduced by approximately 50% along the lesion with an injection of the BAI1 monoclonal antibody and complement. The number of dying cells, identified by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL), was unchanged at this early time point in response to the decrease in Myo/Nog cells. However, increasing the number of Myo/Nog cells within the lesion by injecting BAI1-positive (+) cells isolated from the brains of other animals, significantly reduced cell death and increased the number of NeuN+ neurons compared to brains injected with phosphate buffered saline or exogenous BAI1-negative cells. These findings demonstrate that Myo/Nog cells rapidly react to injury within the brain and increasing their number within the lesion is neuroprotective.


2021 ◽  
Vol 28 (4) ◽  
pp. 279-296
Author(s):  
Jin-Woo Kim ◽  
Mi Kyung Kwak ◽  
Jeong Joon Han ◽  
Sung-Tak Lee ◽  
Ha Young Kim ◽  
...  

Antiresorptives are the most widely prescribed drugs for the treatment of osteoporosis. They are also used in malignant bone metastases, multiple myeloma, and Paget's disease, and provide therapeutic efficacy on those diseases. However, it was reported that the occurrence of osteonecrosis of the jaw (ONJ) could be related to antiresorptive exposures, and there have been many cases regarding this issue. Therefore, a clearer definition and treatment guidelines were needed for this disease. The American Society for Bone and Mineral Research and the Amnerican Association of Oral and Maxillofacial Surgeons reported statements on bisphosphonate-related ONJ (BRONJ), and a revised version was recently presented. In the revised edition, the diagnosis BRONJ was changed to medication-related ONJ (MRONJ), which reflects consideration of the fact that ONJ also occurs for denosumab, a bone resorption inhibitor of the receptor activator of the nuclear factor-κB ligand antibody family, and bevacizumab, an anti-angiogenesis inhibitor. The Korean Society for Bone and Mineral Research and the Korean Association of Oral and Maxillofacial Surgeons had collectively formed a task force for the preparation of an official statement on MRONJ based on a previous position paper in 2015. The task force reviewed current knowledge and coordinated dental and medical opinions to propose the guideline customized for the local Korean situation.


2021 ◽  
Vol 23 (3) ◽  
pp. 425-427
Author(s):  
Elena V. Reutova ◽  
Konstantin K. Laktionov

The possibilities of treatment of patients with metastatic non-small cell lung cancer have significantly expanded in the recent years. Several combined regimens of chemoimmunotherapy are currently being proposed as the first line, some patients with PD-L1 overexpression may be prescribed pembrolizumab or atezolizumab in monotherapy. Standard platinum-containing chemotherapy (PCT) has lost its position and is relevant only for contraindications to immuno-oncological (IO) drugs. The change in the standart of the first line inevitably led to the search for new optimal modes of the second line. The strategy of "angio-immunogenic switching" is promising after progression on the regimens with IO, anti-angiogenic drugs are used. Nintedanib a multikinase angiogenesis inhibitor in combination with docetaxel is a standard second-line therapy option in patients with lung adenocarcinoma after progression on PCT. The effectiveness of this regimen is being studied in a prospective non-interventional VARGADO study. The patients were divided into 3 cohorts, depending on which regimen was used earlier one line of PCT or PCT, followed by IO or chemoimmunotherapy. The results showed that the combination of docetaxel + nintedanib was effective both as a third line (after PCT and IO), and in the second after chemoimmunotherapy. The research is ongoing.


2021 ◽  
Vol 9 ◽  
Author(s):  
Moran Sun ◽  
Yuyang Wang ◽  
Minghua Yuan ◽  
Qing Zhao ◽  
Yixin Zhang ◽  
...  

A library of new heteroaromatic ring-linked chalcone analogs were designed and synthesized of these, compound 7m with α-CH3 substitution and bearing a benzofuran ring, displaying the most potent activity, with IC50 values of 0.07–0.183 µM against three cancer cells. Its low cytotoxicity toward normal human cells and strong potency on drug-resistant cells revealed the possibility for cancer therapy. It also could moderately inhibit in vitro tubulin polymerization with an IC50 value of 12.23 µM, and the disruption of cellular architecture in MCF-7 cells was observed by an immunofluorescence assay. Cellular-based mechanism studies elucidated that 7m arrested the cell cycle at the G2/M phase and induced apoptosis by regulating the expression levels of caspases and PARP protein. Importantly, the compound 7 m was found to inhibit HUVEC tube formation, migration, and invasion in vitro. In vivo assay showed that 7m could effectively destroy angiogenesis of zebrafish embryos. Furthermore, our data suggested that treatment with 7m significantly reduced MCF-7 cell metastasis and proliferation in vitro and in zebrafish xenograft. Collectively, this work showed that chalcone hybrid 7m deserves further investigation as dual potential tubulin polymerization and angiogenesis inhibitor.


2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi38-vi39
Author(s):  
Satoru Osuka ◽  
Liquan Yang ◽  
Dan Zhu ◽  
Hideharu Hashimoto ◽  
Erwin G Van Meir

Abstract Medulloblastoma (MB) is the most common malignant brain tumor in children. MB tends to metastasize to the brain meninges and subarachnoid space and the spinal cord. Leptomeningeal metastasis is frequently found at initial diagnosis and leads to tumor relapse after standard treatment. Leptomeningeal metastasis remains a major challenge and is related with poor outcome. Acquiring a better knowledge of molecular defects underlying metastatic disease is essential for the development of effective therapies. Brain-specific Angiogenesis Inhibitor 1 (BAI1/ADGRB1) is a transmembrane receptor of the adhesion GPCR family widely expressed in normal brain, but its expression is lost in the majority of medulloblastoma through epigenetic silencing. We reported that BAI1 protects p53 from Mdm2-mediated degradation and regulate tumor growth in medulloblastoma (Zhu D. et al, Cancer Cell, 2018). However, it is unclear whether BAI1 loss is important for tumor invasion and the mesenchymal phenotype in MB. Microarray analysis of the published MB dataset revealed that low BAI1 mRNA expression correlates with poor outcome and with expression of many key mesenchymal genes, including Fibronectin1, SLUG, and TWIST1. Restoration of BAI1 expression in human MB cells suppresses mesenchymal gene expression in culture, and dramatically decreases brain tumor invasion. Mechanistically, we found that the N-terminal thrombospondin type 1 repeat (TSR#1) of BAI1 inhibits the maturation process of TGFβ1, a key growth factor involved in EMT. BAI1 is silenced epigenetically in MB cells by methylated CpG-binding protein MBD2, and its expression can be reactivated by KCC-07, a blood-brain barrier permeable MBD2 inhibitor. We found that restoration of BAI1 expression by KCC-07 treatment dramatically reduced tumor cell invasion of MB cells. These experiments demonstrate that epigenetic silencing of BAI1 is important for activation of the MB invasive phenotype through TGFβ1 pathway activation. Epigenetic targeting of this process by KCC-07 can reduce MB invasion.


2021 ◽  
pp. 27-32
Author(s):  
R.M. Zainullin ◽  

Purpose. Improving the efficiency of surgical treatment of patients with diabetic macular edema and epiretinal membrane. Material and methods. Clinical studies were based on the analysis of morphological and functional parameters of the central retina. Patients with diffuse diabetic macular edema (DME) and epiretinal membrane (ERM) made up group A (main) of 96 people (96 eyes). Group B (control) included 22 patients (44 eyes) without ophthalmological diseases. Depending on the chosen method of surgical treatment, patients in group A were divided into three subgroups. Results. According to the data of optical coherence tomography, it was revealed that the average index of retinal thickness as a result of edema increased by 1.35 times (p=0.011) compared with group B. When conducting microperimetry in the macular zone in patients of group A, the total light sensitivity was reduced in 1.88 times compared with group B (p=0.028). Comparative analysis of long-term results of surgical treatment of patients with DMO and ERM showed that complex simultaneous vitrectomy and administration of an angiogenesis inhibitor is preferable compared to delayed administration of drugs, which is confirmed by a decrease in the total thickness of the retina in 78.3% of cases, preservation of the total photosensitivity of the central part of the retina on average, up to 15.3±3.24 dB, visual acuity - up to 0.51±0.22, no recurrence of edema in 63.4% of patients and the development of ERM - in 100% of cases. Conclusion. If the central thickness of the retina at the preoperative stage is less than 400 microns, it is possible to use a step-by-step method (vitrectomy + intravitreal administration of an angiogenesis inhibitor after 1 month). The use of the proposed one-step operation technique is preferable when the retina thickness is more than 400 microns. Vitrectomy with peeling of the internal limiting membrane in patients with cysts in the retinal edema zone with a diameter of more than 200 µm does not lead to a positive anatomical and functional result. Key words: diabetic macular edema, angiogenesis inhibitor, vitrectomy, microperimetry, epiretinal membrane.


2021 ◽  
Author(s):  
SABELO HADEBE ◽  
Anca Flavia Savulescu ◽  
Jermaine Khumalo ◽  
Katelyn Jones ◽  
Sandisiwe Mangali ◽  
...  

Abstract Allergic asthma is a disease driven by T helper 2 (Th2) cells, eosinophilia, airway hyperresponsiveness (AHR) and IgE-secreting B cells. Asthma is largely controlled by corticosteroids and β2 adregenic receptor agonists that target and relax airway smooth muscle (ASM). Immunoglobulin M (IgM) isotype secreted by naïve B cells is important for class switching but may have other undefined functions. We investigated the role of IgM in a house dust mite (HDM)-induced Th2 allergic asthma model by sensitising wild type (WT) and IgM-deficient (IgM-/-) mice with HDM. We validated our findings using CRISPR and single cell force cytometry in human ASM. We found IgM to be essential in AHR but not Th2 airway inflammation or eosinophilia. RNA sequencing of lung tissue suggested that IgM regulated AHR through modulating brain-specific angiogenesis inhibitor 1-associated protein 2-like protein 1 (Baiap2l1) and erythroid differentiation regulator 1 (Erdr1). Deletion of BAIAP2L1 and ERDR1 reduced human ASM contraction when stimulated with TNF-α. These are unprecedented findings and have implications in future treatment of asthma beyond current therapies.


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