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Journal articles on the topic 'Folate receptor α'

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Author: Grafiati

Published: 11 March 2023

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1

Boss, Silvan D., and Simon Mensah Ametamey. "Development of Folate Receptor−Targeted PET Radiopharmaceuticals for Tumor Imaging—A Bench-to-Bedside Journey." Cancers 12, no. 6 (June 9, 2020): 1508. http://dx.doi.org/10.3390/cancers12061508.

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The folate receptor-α (FR-α) is overexpressed in many epithelial cancers, including ovary, uterus, kidneys, breast, lung, colon and prostate carcinomas, but shows limited expression in normal tissues such as kidneys, salivary glands, choroid plexus and placenta. FR-α has therefore emerged as a promising target for the delivery of therapeutic and imaging agents to FR-positive tumors. A series of folate-based PET (positron emission tomography) radiopharmaceuticals have been developed for the selective targeting of FR-positive malignancies. This review provides an overview on the research progress made so far regarding the design, radiosynthesis and the utility of the folate-derived PET radioconjugates for targeting FR-positive tumors. For the most part, results from folate radioconjugates labeled with fluorine-18 (t1/2 = 109.8 min) and gallium-68 (t1/2 = 67.7 min) have been presented but folates labeled with “exotic” and new PET radionuclides such as copper-64 (t1/2 = 12.7 h), terbium-152 (t1/2 = 17.5 h), scandium-44 (t1/2 = 3.97 h), cobalt-55 (t1/2 = 17.5 h) and zirconium-89 (t1/2 = 78.4 h) are also discussed. For tumor imaging, none of the reported PET radiolabeled folates reported to date has made the complete bench-to-bedside journey except [18F]AzaFol, which made it to patients with metastatic ovarian and lung cancers in a multicenter first-in-human trial. In the near future, however, we expect more clinical trials with folate-based PET radiopharmaceuticals given the increasing clinical interest in imaging and the treatment of FR-related malignancies.

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2

Høier-Madsen, Mimi, Jan Holm, and Steen I. Hansen. "α Isoforms of soluble and membrane-linked folate-binding protein in human blood." Bioscience Reports 28, no. 3 (June 1, 2008): 153–60. http://dx.doi.org/10.1042/bsr20070033.

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The high-affinity FBP/FR (folate-binding protein/folate receptor) is expressed in three isoforms. FRα and FRβ are attached to cell membranes by hydrophobic GPI (glycosylphosphatidylinositol) anchors, whereas FBPγ is a secretory protein. Mature neutrophil granulocytes contain a non-functional FRβ on the surface, and, in addition, nanomolar concentrations of a secretory functional FBP (29 kDa) can be present in the secondary granules. A statistically significant correlation between the concentrations of functional FBP, probably a γ isoform, in granulocytes and serum supported the hypothesis that serum FBP (29 kDa) mainly originates from neutrophils. The presence of FBP/FRα isoforms were established for the first time in human blood using antibodies specifically directed against human milk FBPα. The α isoforms identified on erythrocyte membranes, and in granulocytes and serum, only constituted an almost undetectable fraction of the functional FBP. The FBPα in neutrophil granulocytes was identified as a cytoplasmic component by indirect immunofluorescence. Gel filtration of serum revealed a peak of FBPα (>120 kDa), which could represent receptor fragments from decomposed erythrocytes and granulocytes. The soluble FBPs may exert bacteriostatic effects and protect folates in plasma from biological degradation, whereas FRs on the surface of blood cells could be involved in intracellular folate uptake or serve as signal proteins. The latter receptors have also been used for therapeutic targeting in malignancy.

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3

Scaranti, Mariana, Elena Cojocaru, Susana Banerjee, and Udai Banerji. "Exploiting the folate receptor α in oncology." Nature Reviews Clinical Oncology 17, no. 6 (March 9, 2020): 349–59. http://dx.doi.org/10.1038/s41571-020-0339-5.

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4

Bremer, Ryan E., Tatiana S. Scoggin, Elizabeth B. Somers, Daniel J. O'Shannessy, and David E. Tacha. "Interobserver Agreement and Assay Reproducibility of Folate Receptor α Expression in Lung Adenocarcinoma: A Prognostic Marker and Potential Therapeutic Target." Archives of Pathology & Laboratory Medicine 137, no. 12 (April 9, 2013): 1747–52. http://dx.doi.org/10.5858/arpa.2013-0039-oa.

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Context.—Lung cancer is the leading cause of cancer deaths in the United States and globally. Folate-targeted drugs are among the promising new targeted therapies for lung cancer, provided predictive biomarkers can be identified for optimal patient selection. Objective.—To evaluate the interobserver agreement and reproducibility of an immunohistochemistry assay for folate receptor α as a potential predictive marker for folate-targeted therapies. Design.—Immunohistochemistry using anti–folate receptor α antibody 26B3 was performed on formalin-fixed, paraffin-embedded tissues. The M-score, a semiquantitative measure of staining intensity and proportion of tumor cells staining, was determined for each specimen. Interobserver agreement was assessed using lung adenocarcinoma specimens stained at a single site and evaluated by 3 independent pathologists. Interinstrument reproducibility assessed 20 specimens stained by 3 different automated stainers. Interlaboratory agreement was determined on 5 specimens, repeatedly stained on each of 5 days, at 3 different study sites. Results.—Folate receptor α expression was identified in 39 of 54 cases of lung adenocarcinoma (72%) and 4 of 37 cases of lung squamous cell carcinoma (11%). Agreement among 3 pathologists was found in 24 of 26 cases (92%). Interinstrument reproducibility was observed in 19 of 20 cases (95%). Agreement among 3 laboratories was found for 49 of 50 specimens (98%). Conclusions.—Immunostaining of folate receptor α in lung adenocarcinomas is reproducible across staining platforms and among laboratories. Agreement among pathologists is achieved using a semiquantitative scoring method. An accurate and convenient method for determining folate receptor α expression offers a potentially invaluable tool for selecting patients for folate-targeted therapies.

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5

Bartouskova, Marie, Bohuslav Melichar, and Beatrice Mohelnikova-Duchonova. "Folate receptor: a potential target in ovarian cancer." Pteridines 26, no. 1 (March 1, 2015): 1–12. http://dx.doi.org/10.1515/pterid-2014-0013.

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AbstractOvarian cancer is the most frequent cause of gynecological cancer-related death. Unfortunately, many patients are diagnosed at an advanced stage and have a poor prognosis. The standard treatment for advanced disease involves maximal cytoreductive surgery and chemotherapy based on platinum compounds and taxanes. Patients presenting at an advanced stage have a higher risk of recurrence. The development of drug resistance currently represents a major obstacle in the systematic treatment and, therefore, the discovery of new anticancer agents and approaches should improve the poor prognosis of these patients. Folate receptor α is overexpressed in epithelial ovarian cancer (EOC), but has limited expression in nonmalignant human tissues. The degree of folate receptor expression corresponds with the stage and grade of the disease. Because of this, folate receptor α seems to be a potential therapeutic target for the treatment of ovarian cancer. Currently, several approaches have been studied to target this protein in ovarian cancer treatment. This review summarizes current knowledge about the potential usage of folate receptors as prognostic and predictive biomarkers as well as their role in the management and targeted therapy of ovarian cancer.

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6

Miotti, S., M. Bagnoli, A. Tomassetti, M. I. Colnaghi, and S. Canevari. "Interaction of folate receptor with signaling molecules lyn and G(alpha)(i-3) in detergent-resistant complexes from the ovary carcinoma cell line IGROV1." Journal of Cell Science 113, no. 2 (January 15, 2000): 349–57. http://dx.doi.org/10.1242/jcs.113.2.349.

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Using as a model the ovary carcinoma cell line IGROV1, we analyzed the partitioning of the glycosyl-phosphatidylinositol-anchored folate receptor into lipid rafts based on its relative detergent insolubility, with a focus on physically and functionally associated signaling molecules. A variable amount (40-60%) of folate receptor was found in low-density Triton X-100 insoluble complexes together with subunits of heterotrimeric G-proteins and the src-family non-receptor tyrosine kinases p53-56 lyn. In the same fraction the structural component of caveolae, caveolin, was not detected at the protein level, although the corresponding mRNA was detected in trace amounts. Comodulation of folate receptor and signalling molecules was observed in the detergent-insoluble complexes during cell proliferation or induced by phosphatidylinositol-specific phospholipase C treatment or by interaction with anti-folate receptor monoclonal antibodies. Moreover, complexes of folate receptor, lyn and the G(α)(i-3) subunit were immunoprecipitated using either anti-folate receptor or anti-lyn antibodies. In vitro kinase assay of the immunoprecipitates revealed stimulation of phosphorylation of common and specific proteins. In particular, the p53 form of lyn appeared to be enriched and phosphorylated in the anti-folate receptor MOv19 monoclonal antibody immunoprecipitate, whereas a 40 kDa band common to anti-folate receptor and anti-lyn immunoprecipitates was the phosphorylated form of the G(α)(i-3) subunit. These findings point to the functional interaction between folate receptor and associated signaling molecules.

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7

Nogueira, Eugénia, Marisa P. Sárria, Nuno G. Azoia, Egipto Antunes, Ana Loureiro, Diana Guimarães, Jennifer Noro, Alexandra Rollett, Georg Guebitz, and Artur Cavaco-Paulo. "Internalization of Methotrexate Conjugates by Folate Receptor-α." Biochemistry 57, no. 49 (November 19, 2018): 6780–86. http://dx.doi.org/10.1021/acs.biochem.8b00607.

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8

Cagle, Philip T., Qihui “Jim” Zhai, Linda Murphy, and Philip S. Low. "Folate Receptor in Adenocarcinoma and Squamous Cell Carcinoma of the Lung: Potential Target for Folate-Linked Therapeutic Agents." Archives of Pathology & Laboratory Medicine 137, no. 2 (February 1, 2013): 241–44. http://dx.doi.org/10.5858/arpa.2012-0176-oa.

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Context.— Lung cancer is the number one cause of cancer deaths in the United States and globally. The advent of targeted therapies has offered a new treatment paradigm for lung cancer, but currently validated and emerging drugs are effective in only a small minority of lung cancers, predominantly adenocarcinomas. Folate receptors can serve as targets for drugs attached to folate and are overexpressed in many cancers. Objective.— To determine the frequency of folate receptor overexpression in lung cancers of different cell types as potential targets for folate-linked therapy. Design.— High-density tissue microarrays were constructed from archival formalin-fixed, paraffin-embedded resection specimens from 188 primary stage I or stage II adenocarcinomas or squamous cell carcinomas of the lung with three 0.1-cm cores from each tumor. Tissue microarrays were immunostained for folate receptor α with mAb343 and the results scored (0 to 1+ = weak expression, 2+ to 3+ = strong expression). Results.— Eighty-four of 117 (72%) of the adenocarcinomas were strongly positive for the folate receptor, and 36 of 71 (51%) of the squamous cell carcinomas were strongly positive for the folate receptor. Conclusions.— Our data indicate that a large percentage of lung cancers, including squamous cell carcinomas in addition to adenocarcinomas, strongly express folate receptor. This suggests that folate-linked targeted therapy can potentially be used to treat the majority of lung cancers, both adenocarcinomas and, particularly, squamous cell carcinomas, that do not respond to current targeted therapies.

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9

Kim, Hye Won, Yun Jung Choi, Ki Nam Kim, Tsunenobu Tamura, and Namsoo Chang. "Effect of paternal folate deficiency on placental folate content and folate receptor α expression in rats." Nutrition Research and Practice 5, no. 2 (2011): 112. http://dx.doi.org/10.4162/nrp.2011.5.2.112.

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10

Samodelov, Sophia L., Zhibo Gai, Gerd A. Kullak-Ublick, and Michele Visentin. "Renal Reabsorption of Folates: Pharmacological and Toxicological Snapshots." Nutrients 11, no. 10 (October 2, 2019): 2353. http://dx.doi.org/10.3390/nu11102353.

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Folates are water-soluble B9 vitamins that serve as one-carbon donors in the de novo synthesis of thymidylate and purines, and in the conversion of homocysteine to methionine. Due to their key roles in nucleic acid synthesis and in DNA methylation, inhibiting the folate pathway is still one of the most efficient approaches for the treatment of several tumors. Methotrexate and pemetrexed are the most prescribed antifolates and are mainly used in the treatment of acute myeloid leukemia, osteosarcoma, and lung cancers. Normal levels of folates in the blood are maintained not only by proper dietary intake and intestinal absorption, but also by an efficient renal reabsorption that seems to be primarily mediated by the glycosylphosphatidylinositol- (GPI) anchored protein folate receptor α (FRα), which is highly expressed at the brush-border membrane of proximal tubule cells. Folate deficiency due to malnutrition, impaired intestinal absorption or increased urinary elimination is associated with severe hematological and neurological deficits. This review describes the role of the kidneys in folate homeostasis, the molecular basis of folate handling by the kidneys, and the use of high dose folic acid as a model of acute kidney injury. Finally, we provide an overview on the development of folate-based compounds and their possible therapeutic potential and toxicological ramifications.

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11

Cardella, Davide, Wenjing Deng, Louis Y. P. Luk, and Yu-Hsuan Tsai. "Effect of Trimethine Cyanine Dye- and Folate-Conjugation on the In Vitro Biological Activity of Proapoptotic Peptides." Biomolecules 12, no. 5 (May 20, 2022): 725. http://dx.doi.org/10.3390/biom12050725.

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Despite continuous advances, anticancer therapy still faces several technical hurdles, such as selectivity on cellular and subcellular targets of therapeutics. Toward addressing these limitations, we have combined the use of proapoptotic peptides, trimethine cyanine dye, and folate to target the mitochondria of tumor cells. A series of proapoptotic peptides and their conjugates with a cyanine dye and/or folate were synthesized in the solid phase, and their toxicity in different human cell lines was assessed. Cyanine-bearing conjugates were found to be up to 100-fold more cytotoxic than the parent peptides and to localize in mitochondria. However, the addition of a folate motif did not enhance the potency or selectivity of the resulting conjugates toward tumor cells that overexpress folate receptor α. Furthermore, while dual-labeled constructs were also found to localize within the target organelle, they were not generally selective towards folate receptor α-positive cell lines in vitro.

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12

Driver, Brandon R., Roberto Barrios, Yimin Ge, Abida Haque, David Tacha, and Philip T. Cagle. "Folate Receptor α Expression Level Correlates With Histologic Grade in Lung Adenocarcinoma." Archives of Pathology & Laboratory Medicine 140, no. 7 (November 24, 2015): 682–85. http://dx.doi.org/10.5858/arpa.2015-0431-oa.

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Context.—Folate receptor α (FRA) is a glycosylphosphatidylinositol-anchored high-affinity folate receptor that localizes to the apical surface of epithelia when it is expressed in normal tissue. Unlike normal tissues, FRA may localize to the basolateral side in tumors. These features make FRA an attractive drug target, and several FRA-targeted drugs have been developed and are in phases of clinical testing. Folate receptor α protein expression shows intertumoral variability that may correlate with response to therapy and to clinicopathologic parameters. Using immunohistochemistry, a recent study of breast carcinomas found FRA protein expression was associated with triple-negative status and high histologic grade in breast cancer. Although a prior study of lung adenocarcinomas found the expression level of the gene encoding FRA, FOLR1, was significantly increased in low-histologic-grade tumors compared to high-histologic-grade tumors, the relationship between FRA protein expression and histologic grade has not been reported for lung adenocarcinomas. Objective.—To investigate the relationship between FRA protein expression level and clinicopathologic parameters in lung adenocarcinomas, including histologic grade, by performing immunohistochemistry for FRA on a cohort of non–small cell lung carcinomas. Design.—High-density tissue microarrays constructed from 188 non–small cell lung carcinomas and used in prior studies were immunostained with FRA-specific antibody clone 26B3. Folate receptor α membranous staining intensity was given a semiquantitative score from 0 to 3+ for triplicate cores of tumor and averaged for each tumor. An average semiquantitative score from 0 to 1.4 was considered low expression, and an average semiquantitative score greater than 1.4 was considered high expression. Results.—The majority (60 of 78; 77%) of lung adenocarcinomas and a minority (4 of 41; 10%) of lung squamous cell carcinomas were positive for FRA. Folate receptor α expression in lung adenocarcinomas compared with squamous cell carcinomas was statistically different (P < .001, χ2 test). In lung adenocarcinomas, FRA expression level correlated with histologic grade (P = .005, χ2 test for trend), but no other clinicopathologic parameter. The majority (23 of 27; 85%) of grade 1 adenocarcinomas had high FRA protein expression, whereas approximately half of grade 2 (10 of 19; 53%) and grade 3 (12 of 25; 48%) adenocarcinomas had high FRA protein expression. Out of adenocarcinomas with lepidic growth pattern, 16 of 20 (80%) showed high FRA protein expression. Out of adenocarcinomas with solid growth pattern, 2 of 6 (33%) showed high FRA protein expression. In lung adenocarcinomas, FRA expression level did not correlate with thyroid transcription factor 1, napsin A, or survival. Conclusions.—Folate receptor α protein was expressed in the majority of lung adenocarcinomas and a minority of lung squamous cell carcinomas. Folate receptor α protein expression correlated with histologic grade for lung adenocarcinomas, and the greatest difference was observed between grade 1 and grade 3. Our results indicate that poorly differentiated adenocarcinomas or focuses of poor differentiation in a heterogeneous tumor may lack FRA protein expression and be more likely to be resistant to FRA-targeting drugs.

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13

Jhaveri, Mona S., Antonina S. Rait, Koong-Nah Chung, Jane B. Trepel, and Esther H. Chang. "Antisense oligonucleotides targeted to the human α folate receptor inhibit breast cancer cell growth and sensitize the cells to doxorubicin treatment." Molecular Cancer Therapeutics 3, no. 12 (December 1, 2004): 1505–12. http://dx.doi.org/10.1158/1535-7163.1505.3.12.

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Abstract Folates are essential for cell survival and are required for numerous biochemical processes. The human α isoform folate receptor (αhFR) has a very high affinity for folic acid and is considered an essential component in the cellular accumulation of folates and folate analogues used in chemotherapy. The expression of αhFR is not detected inmost normal tissues. In contrast, high levels of the expression of αhFR have been reported in a variety of cancer cells. The significance of αhFR overexpression in malignant tissues has not been elucidated, but it is possible that it promotes cell proliferation not only by mediating folate uptake but also by generating other regulatory signals. The purpose of the present study was to evaluate αhFR as a potential target for the treatment of breast cancer. Initial studies were done in nasopharyngeal carcinoma (KB) cells, which express high levels of αhFR. In KB cells, antisense oligodeoxyribonucleotides (ODN) complementary to the αhFR gene sequences were found to reduce newly synthesized αhFR protein up to 60%. To examine the effect of αhFR antisense ODNs in a panel of cultured human breast cancer cell lines, we used a tumor cell–targeted, transferrin-liposome–mediated delivery system. The data show that αhFR antisense ODNs induced a dose-dependent decrease in cell survival. Finally, we determined that αhFR antisense ODNs sensitized MDA-MB-435 breast cancer cells by 5-fold to treatment with doxorubicin. The data support the application of αhFR antisense ODNs as a potential anticancer agent in combination with doxorubicin.

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14

Elnakat, Hala, Mesfin Gonit, Marcela D’Alincourt Salazar, Juan Zhang, Venkatesha Basrur, William Gunning, Barton Kamen, and Manohar Ratnam. "Regulation of Folate Receptor Internalization by Protein Kinase C α." Biochemistry 48, no. 34 (September 2009): 8249–60. http://dx.doi.org/10.1021/bi900565t.

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15

Kamen, B. A., and A. K. Smith. "Farletuzumab, an anti-folate receptor α antibody, does not block binding of folate or anti-folates to receptor nor does it alter the potency of anti-folates in vitro." Cancer Chemotherapy and Pharmacology 70, no. 1 (May 27, 2012): 113–20. http://dx.doi.org/10.1007/s00280-012-1890-2.

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16

Mafi, Sarah, Cécile Laroche-Raynaud, Pauline Chazelas, Anne-Sophie Lia, Paco Derouault, Franck Sturtz, Yasser Baaj, et al. "Pharmacoresistant Epilepsy in Childhood: Think of the Cerebral Folate Deficiency, a Treatable Disease." Brain Sciences 10, no. 11 (October 22, 2020): 762. http://dx.doi.org/10.3390/brainsci10110762.

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Cerebral folate deficiency (CFD) is a neurological disorder characterized by low levels of 5-methyltetrahydrofolate (5-MTHF) in the cerebrospinal fluid (CSF). The prevalence of this autosomal recessive disorder is estimated to be <1/1,000,000. Fifteen different pathogenic variants in the folate receptor 1 gene (FOLR1) encoding the receptor of folate α (FRα) have already been described. We present a new pathogenic variation in the FOLR1 in a childhood-stage patient. We aim to establish the core structure of the FRα protein mandatory for its activity. A three-year-old child was admitted at hospital for a first febrile convulsions episode. Recurrent seizures without fever also occurred a few months later, associated with motor and cognitive impairment. Various antiepileptic drugs failed to control seizures. Magnetic resonance imaging (MRI) showed central hypomyelination and biological analysis revealed markedly low levels of 5-MTHF in CSF. Next generation sequencing (NGS) confirmed a CFD with a FOLR1 homozygous variation (c.197 G > A, p.Cys66Tyr). This variation induces an altered folate receptor α protein and underlines the role of a disulfide bond: Cys66-Cys109, essential to transport 5-MTHF into the central nervous system. Fortunately, this severe form of CFD had remarkably responded to high doses of oral folinic acid combined with intravenous administrations.

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17

Xia, Wei, Andrew R. Hilgenbrink, Eric L. Matteson, Michael B. Lockwood, Ji-Xin Cheng, and Philip S. Low. "A functional folate receptor is induced during macrophage activation and can be used to target drugs to activated macrophages." Blood 113, no. 2 (January 8, 2009): 438–46. http://dx.doi.org/10.1182/blood-2008-04-150789.

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Abstract Previous work has demonstrated that a subset of macrophages expresses a folate receptor (FR) that can mediate internalization of folate-linked molecules, including imaging and therapeutic agents. To characterize this subset, macrophages were collected from peritoneal cavities of mice injected with saline, thioglycolate, zymosan, heat-killed or live bacteria, and cell-surface markers that coexpress with FR were identified. Virtually no F4/80+ peritoneal macrophages from saline-injected mice expressed FR, whereas numerous macrophages from mice injected with each inflammatory stimulus expressed FR. Examination of cell differentiation antigens that are up-regulated in FR+ macrophages revealed markers characteristic of an activated state (CD80, CD86, Ly-6C/G), whereas macrophages lacking these activation markers expressed few or no FR. FR+ macrophages also produced tumor necrosis factor-α (TNF-α) and reactive oxygen species, and production of reactive oxygen species correlated linearly with expression of FR. Synovial macrophages collected from arthritic patients were found to bind and internalize folate-linked dyes. Moreover, a folate-linked radioimaging agent was shown to image inflamed joints of rheumatoid arthritic patients. These results suggest that FR constitutes a marker for macrophage activation and that FR+ macrophages can be targeted with folate-linked drugs without promoting drug uptake by nonactivated macrophages. This trial was registered at www.clinicaltrials.gov as #NCT00588393.

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18

Li, Zihou, Xuehua Ma, Yuanzhi Xia, Kun Qian, Ozioma Udochukwu Akakuru, Lijia Luo, Jianjun Zheng, Ping Cui, Zheyu Shen, and Aiguo Wu. "A pH-sensitive polymer based precise tumor targeting strategy with reduced uptake of nanoparticles by non-cancerous cells." Journal of Materials Chemistry B 7, no. 39 (2019): 5983–91. http://dx.doi.org/10.1039/c9tb01202h.

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19

Bueno, Raphael, Krishnarao Appasani, Harriet Mercer, Susan Lester, and David Sugarbaker. "The α folate receptor is highly activated in malignant pleural mesothelioma." Journal of Thoracic and Cardiovascular Surgery 121, no. 2 (February 2001): 225–33. http://dx.doi.org/10.1067/mtc.2001.111176.

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20

Necela, Brian M., Jennifer A. Crozier, Cathy A. Andorfer, Laura Lewis-Tuffin, Jennifer M. Kachergus, Xochiquetzal J. Geiger, Krishna R. Kalari, et al. "Folate Receptor-α (FOLR1) Expression and Function in Triple Negative Tumors." PLOS ONE 10, no. 3 (March 27, 2015): e0122209. http://dx.doi.org/10.1371/journal.pone.0122209.

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Clifton, Guy T., Alan K. Sears, Kevin S. Clive, Jarrod P. Holmes, Elizabeth A. Mittendorf, Constantine G. Ioannides, Sathibalan Ponniah, and George E. Peoples. "Folate receptor α: A storied past and promising future in immunotherapy." Human Vaccines 7, no. 2 (February 2011): 183–90. http://dx.doi.org/10.4161/hv.7.2.13784.

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22

Farran, Batoul, Samet Albayrak, Judith Abrams, Michael A. Tainsky, Nancy K. Levin, Robert Morris, Larry H. Matherly, Manohar Ratnam, and Ira Winer. "Serum folate receptor α (sFR) in ovarian cancer diagnosis and surveillance." Cancer Medicine 8, no. 3 (February 13, 2019): 920–27. http://dx.doi.org/10.1002/cam4.1944.

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Spinella, Michael J., Kevin E. Brigle, Esteban E. Sierra, and I. David Goldman. "Distinguishing between Folate Receptor-α-mediated Transport and Reduced Folate Carrier-mediated Transport in L1210 Leukemia Cells." Journal of Biological Chemistry 270, no. 14 (April 7, 1995): 7842–49. http://dx.doi.org/10.1074/jbc.270.14.7842.

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Díaz-García, Diana, Karla Montalbán-Hernández, Irene Mena-Palomo, Patriciu Achimas-Cadariu, Antonio Rodríguez-Diéguez, Eduardo López-Collazo, Sanjiv Prashar, et al. "Role of Folic Acid in the Therapeutic Action of Nanostructured Porous Silica Functionalized with Organotin(IV) Compounds against Different Cancer Cell Lines." Pharmaceutics 12, no. 6 (June 3, 2020): 512. http://dx.doi.org/10.3390/pharmaceutics12060512.

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The synthesis, characterization and cytotoxic activity against different cancer cell lines of various mesoporous silica-based materials containing folate targeting moieties and a cytotoxic fragment based on a triphenyltin(IV) derivative have been studied. Two different mesoporous nanostructured silica systems have been used: firstly, micronic silica particles of the MSU-2 type and, secondly, mesoporous silica nanoparticles (MSNs) of about 80 nm. Both series of materials have been characterized by different methods, such as powder X-ray diffraction, X-ray fluorescence, absorption spectroscopy and microscopy. In addition, these systems have been tested against four different cancer cell lines, namely, OVCAR-3, DLD-1, A2780 and A431, in order to observe if the size of the silica-based systems and the quantity of incorporated folic acid influence their cytotoxic action. The results show that the materials are more active when the quantity of folic acid is higher, especially in those cells that overexpress folate receptors such as OVCAR-3 and DLD-1. In addition, the study of the potential modulation of the soluble folate receptor alpha (FOLR1) by treatment with the synthesized materials has been carried out using OVCAR-3, DLD-1, A2780 and A431 tumour cell lines. The results show that a relatively high concentration of folic acid functionalization of the nanostructured silica together with the incorporation of the cytotoxic tin fragment leads to an increase in the quantity of the soluble FOLR1 secreted by the tumour cells. In addition, the studies reported here show that this increase of the soluble FOLR1 occurs presumably by cutting the glycosyl-phosphatidylinositol anchor of membrane FR-α and by the release of intracellular FR-α. This study validates the potential use of a combination of mesoporous silica materials co-functionalized with folate targeting molecules and an organotin(IV) drug as a strategy for the therapeutic treatment of several cancer cells overexpressing folate receptors.

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Zhang, Zhang, Jianmin Wang, David E. Tacha, Pamela Li, Ryan E. Bremer, Huijiao Chen, Bing Wei, et al. "Folate Receptor α Associated With Triple-Negative Breast Cancer and Poor Prognosis." Archives of Pathology & Laboratory Medicine 138, no. 7 (July 2014): 890–95. http://dx.doi.org/10.5858/arpa.2013-0309-oa.

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Aboulhagag, Noha Abd ElRahim, Rana Fathy Torky, and Sabah Ahmed Fadel. "Folate receptor α is associated with poor clinicopathological perspectives in breast carcinoma." Pathophysiology 25, no. 1 (March 2018): 71–76. http://dx.doi.org/10.1016/j.pathophys.2018.01.002.

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27

Yao, Congjun, Chheng-Orn Evans, Victoria L. Stevens, Timothy R. Owens, and Nelson M. Oyesiku. "Folate receptor α regulates cell proliferation in mouse gonadotroph αT3-1 cells." Experimental Cell Research 315, no. 18 (November 2009): 3125–32. http://dx.doi.org/10.1016/j.yexcr.2009.05.006.

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28

Kuplennik, Nataliya, Kristina Lang, Robert Steinfeld, and Alejandro Sosnik. "Folate Receptor α-Modified Nanoparticles for Targeting of the Central Nervous System." ACS Applied Materials & Interfaces 11, no. 43 (September 18, 2019): 39633–47. http://dx.doi.org/10.1021/acsami.9b14659.

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Necela, Brian M., Jennifer A. Crozier, Cathy A. Andorfer, Laura Lewis-Tuffin, Jennifer M. Kachergus, Xochiquetzal J. Geiger, Krishna R. Kalari, et al. "Correction: Folate Receptor-α (FOLR1) Expression and Function in Triple Negative Tumors." PLOS ONE 10, no. 4 (April 30, 2015): e0127133. http://dx.doi.org/10.1371/journal.pone.0127133.

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30

Qiu, Zheng, Lijun Xing, Xueqing Zhang, Xu Qiang, Yifeng Xu, Mei Zhang, Zhengpin Zhou, Juan Zhang, Fang Zhang, and Min Wang. "CpG oligodeoxynucleotides augment antitumor efficacy of folate receptor α based DNA vaccine." Oncology Reports 37, no. 6 (May 8, 2017): 3441–48. http://dx.doi.org/10.3892/or.2017.5633.

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Panchabhai, Sonali, Katalin Kelemen, Sinto Sebastian Chirackal, and Rafael Fonseca. "Role Of Folate Receptor Targeted Therapy In Multiple Myeloma." Blood 122, no. 21 (November 15, 2013): 4436. http://dx.doi.org/10.1182/blood.v122.21.4436.4436.

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In multiple myeloma (MM) the interaction of plasma cells, bone marrow stromal cells and tumor associated macrophages (TAMs) plays a significant role in conferring resistance to therapy and in the maintenance of residual disease. Folate receptors (FR) are specifically expressed on metabolically active malignant cells and TAMs and their expression in normal tissues and resting macrophages is limited. FR mediates folate uptake by receptor-mediated endocytosis. This qualifies the receptor to be exploited for drug delivery of folate conjugated cancer therapeutics. Our primary goal in this study is to evaluate the expression of functional FR in MM cells and TAMs with a view to exploit this for folate conjugated targeted therapy for MM. First we evaluated the presence of TAMs in paraffin embedded bone marrow slides of newly diagnosed MM patients with CD68 (pan-Macrophage marker) and CD163 antibodies (specific marker of TAMs) and found extensive infiltration of macrophages in bone marrow from MM patients. Next to evaluate expression of FR in MM cells, we employed an FR antibody and evaluated MM cell lines with immunoblot, flow cytometry and confocal microscopy. In a panel of ten MM cell lines, we found that out of the three FR isoforms (α, β and γ), FR beta (FR-β) is expressed by all of them. Next to test whether this expressed receptor is indeed functional, we incubated the cells with folate deficient media, added different concentrations of EC17 (folate conjugated to FITC, Endocyte Inc.) to the medium and looked for the uptake by flow cytometry after washing off the drug at different time points (after 10, 20, 40 and 60 min).We observed that the uptake begins in 10 min and is saturated at 1 hour with 100nM Folate-FITC. With confocal imaging, Folate-FITC was found in the cytoplasm of MM cells suggesting internalization of Folate-FITC and localization in the cytoplasm. In addition to myeloma cell lines, we also confirmed the uptake of Folate-FITC in CD138+ plasma cells of a newly diagnosed myeloma patient by flow cytometry. This strongly suggests that MM cells express functional FR-β. To test the specificity of this FR mediated uptake, we pre-incubated cells with 0.1mM folic acid in medium for 30 min and then added EC17. This maneuver blocked the activity mediated by FR and no uptake was observed , which proves that the Folate-FITC is internalized only through the FR. To evaluate the expression of FR in-vivo samples, we stained paraffin embedded bone marrow slides of newly diagnosed MM patients with FR-β antibody and TAM specific markers. We observe that FR is expressed on both MM cells as well as TAMs. To assess the endurance of cytotoxic effect of folate conjugated chemotherapeutic agents, we treated MM cell lines with folate conjugated vinka alkaloids and compared them to unconjugated drug and found no significant difference in their action suggesting conjugation with folate does not alter its efficacy. To assess potential toxicity of folate conjugated therapeutics, we obtained CD34+ cells and looked for the uptake of Folate-FITC with flow cytometry. We found no uptake and this is in line with previous reports suggesting that CD34 positive cells express nonfunctional FR. So we propose that FR qualify as potential targets for cancer treatment. Folate targeted therapy using folate-conjugated drugs which can selectively act against both MM cells and supporting TAMs has the potential of specific anti-MM tumoricidal activity. This therapeutic approach would broaden the use of drugs that could be conjugated with folate for MM therapy. Additionally assessment of TAMs in bone marrow sections of MM patients would add another feature for grading, classifying and prognosticating MM. Disclosures: Fonseca: Cylene: Research Funding; AMGEN: Consultancy; Millennium: Consultancy; Binding Site: Consultancy; Onyx: Consultancy, Research Funding; Lilly: Consultancy; BMS: Consultancy; Genzyme: Consultancy; Celgene: Consultancy; Medtronic: Consultancy; Otsuka: Consultancy; Prognostication of MM based on genetic categorization of the disease: Prognostication of MM based on genetic categorization of the disease, Prognostication of MM based on genetic categorization of the disease Patents & Royalties.

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32

Schaber, Ethan N., Nikoleta Ivanova, Stoyan Iliev, Jasmina Petrova, Gergana Gocheva, Galia Madjarova, and Anela Ivanova. "Initial Stages of Spontaneous Binding of Folate-Based Vectors to Folate Receptor-α Observed by Unbiased Molecular Dynamics." Journal of Physical Chemistry B 125, no. 28 (July 12, 2021): 7598–612. http://dx.doi.org/10.1021/acs.jpcb.1c00488.

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33

Pillai, Radhakrishna G., Martin Forster, Meg Perumal, Fraser Mitchell, Julius Leyton, Franklin I. Aibgirhio, Oksana Golovko, Ann L. Jackman, and Eric O. Aboagye. "Imaging Pharmacodynamics of the α-Folate Receptor–Targeted Thymidylate Synthase Inhibitor BGC 945." Cancer Research 68, no. 10 (May 15, 2008): 3827–34. http://dx.doi.org/10.1158/0008-5472.can-08-0135.

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34

Piñuñuri, R., E. Castaño-Moreno, M. N. Llanos, and A. M. Ronco. "Epigenetic regulation of folate receptor-α (FOLR1) in human placenta of preterm newborns." Placenta 94 (May 2020): 20–25. http://dx.doi.org/10.1016/j.placenta.2020.03.009.

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35

Shia, Jinru, David S. Klimstra, James R. Nitzkorski, Philip S. Low, Mithat Gonen, Ron Landmann, Martin R. Weiser, et al. "Immunohistochemical expression of folate receptor α in colorectal carcinoma: patterns and biological significance." Human Pathology 39, no. 4 (April 2008): 498–505. http://dx.doi.org/10.1016/j.humpath.2007.09.013.

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36

D'Angelica, Michael, John Ammori, Mithat Gonen, David S. Klimstra, Philip S. Low, Linda Murphy, Martin R. Weiser, et al. "Folate receptor-α expression in resectable hepatic colorectal cancer metastases: patterns and significance." Modern Pathology 24, no. 9 (May 13, 2011): 1221–28. http://dx.doi.org/10.1038/modpathol.2011.82.

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37

Wang, C., Y. Jiang, X. Fei, and Y. Gu. "Design and interaction mechanism of ligand targeted with folate receptor α and β." Journal of Physical Organic Chemistry 31, no. 1 (May 31, 2017): e3719. http://dx.doi.org/10.1002/poc.3719.

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38

Wang, Hui, Xuan Zheng, Frederick G. Behm, and Manohar Ratnam. "Differentiation-independent retinoid induction of folate receptor type β, a potential tumor target in myeloid leukemia." Blood 96, no. 10 (November 15, 2000): 3529–36. http://dx.doi.org/10.1182/blood.v96.10.3529.

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Abstract Folate receptor (FR) type β is expressed in the myelomonocytic lineage, predominantly during neutrophil maturation and in myeloid leukemias. FR-β expression was elevated up to 20-fold by all-trans retinoic acid (ATRA) in KG-1 myeloid leukemia cells in a dose-dependent and reversible manner in the absence of terminal differentiation or cell growth inhibition. ATRA also increased FR-β expression in vitro in myeloid leukemia cells from patient marrow. FR-β was not up-regulated in KG-1 cells treated with phorbol ester, dexamethasone, 1,25-dihydroxy vitamin D3, or transforming growth factor β. ATRA did not induce FR-β expression in receptor negative cells of diverse origin. The ATRA-induced increase in FR-β expression in KG-1 cells occurred at the level of messenger RNA synthesis, and in 293 cells containing a stably integrated FR-β promoter–luciferase reporter construct, ATRA induced expression of the reporter. From experiments using retinoid agonists and antagonists and from cotransfection studies using the FR-β promoter and expression plasmids for the nuclear receptors retinoic acid receptor (RAR)α, RARβ, or RARγ, it appears that the retinoid effect on FR-β expression could be mediated by ligand binding to RARs α, β, or γ, but not to retinoid X receptors. Furthermore, there was apparent cross-talk between RARα and RARγ selective agonists or antagonists, suggesting a common downstream target for RAR isoforms in inducing FR-β expression. Thus, blocks in the RARα-specific pathway of retinoid-induced differentiation may be bypassed during retinoid induction of FR-β expression. The results suggest that to facilitate FR-targeted therapies, retinoids may be used to modulate FR-β expression in myeloid leukemia cells refractory to retinoid differentiation therapy.

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39

Wang, Hui, Xuan Zheng, Frederick G. Behm, and Manohar Ratnam. "Differentiation-independent retinoid induction of folate receptor type β, a potential tumor target in myeloid leukemia." Blood 96, no. 10 (November 15, 2000): 3529–36. http://dx.doi.org/10.1182/blood.v96.10.3529.h8003529_3529_3536.

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Folate receptor (FR) type β is expressed in the myelomonocytic lineage, predominantly during neutrophil maturation and in myeloid leukemias. FR-β expression was elevated up to 20-fold by all-trans retinoic acid (ATRA) in KG-1 myeloid leukemia cells in a dose-dependent and reversible manner in the absence of terminal differentiation or cell growth inhibition. ATRA also increased FR-β expression in vitro in myeloid leukemia cells from patient marrow. FR-β was not up-regulated in KG-1 cells treated with phorbol ester, dexamethasone, 1,25-dihydroxy vitamin D3, or transforming growth factor β. ATRA did not induce FR-β expression in receptor negative cells of diverse origin. The ATRA-induced increase in FR-β expression in KG-1 cells occurred at the level of messenger RNA synthesis, and in 293 cells containing a stably integrated FR-β promoter–luciferase reporter construct, ATRA induced expression of the reporter. From experiments using retinoid agonists and antagonists and from cotransfection studies using the FR-β promoter and expression plasmids for the nuclear receptors retinoic acid receptor (RAR)α, RARβ, or RARγ, it appears that the retinoid effect on FR-β expression could be mediated by ligand binding to RARs α, β, or γ, but not to retinoid X receptors. Furthermore, there was apparent cross-talk between RARα and RARγ selective agonists or antagonists, suggesting a common downstream target for RAR isoforms in inducing FR-β expression. Thus, blocks in the RARα-specific pathway of retinoid-induced differentiation may be bypassed during retinoid induction of FR-β expression. The results suggest that to facilitate FR-targeted therapies, retinoids may be used to modulate FR-β expression in myeloid leukemia cells refractory to retinoid differentiation therapy.

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40

Chancy, Christy D., Ramesh Kekuda, Wei Huang, Puttur D. Prasad, Jean-Marc Kuhnel, Francis M. Sirotnak, Penny Roon, Vadivel Ganapathy, and Sylvia B. Smith. "Expression and Differential Polarization of the Reduced-folate Transporter-1 and the Folate Receptor α in Mammalian Retinal Pigment Epithelium." Journal of Biological Chemistry 275, no. 27 (April 27, 2000): 20676–84. http://dx.doi.org/10.1074/jbc.m002328200.

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41

Unida, Valeria, Giulia Vindigni, Sofia Raniolo, Carmine Stolfi, Alessandro Desideri, and Silvia Biocca. "Folate-Functionalization Enhances Cytotoxicity of Multivalent DNA Nanocages on Triple-Negative Breast Cancer Cells." Pharmaceutics 14, no. 12 (November 26, 2022): 2610. http://dx.doi.org/10.3390/pharmaceutics14122610.

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DNA is an excellent programmable polymer for the generation of self-assembled multivalent nanostructures useful for biomedical applications. Herein, we developed (i) folate-functionalized nanocages (Fol-NC), very efficiently internalized by tumor cells overexpressing the α isoform of the folate receptor; (ii) AS1411-linked nanocages (Apt-NC), internalized through nucleolin, a protein overexpressed in the cell surface of many types of cancers; and (iii) nanostructures that harbor both folate and AS1411 aptamer functionalization (Fol-Apt-NC). We analyzed the specific miRNA silencing activity of all types of nanostructures harboring miRNA sequestering sequences complementary to miR-21 and the cytotoxic effect when loaded with doxorubicin in a drug-resistant triple-negative breast cancer cell line. We demonstrate that the presence of folate as a targeting ligand increases the efficiency in miR-21 silencing compared to nanocages functionalized with AS1411. Double-functionalized nanocages (Fol-Apt-NC), loaded with doxorubicin, resulted in an increase of over 51% of the cytotoxic effect on MDA-MB-231 cells compared to free doxorubicin, demonstrating, besides selectivity, the ability of nanocages to overcome Dox chemoresistance. The higher efficiency of the folate-functionalized nanocages is due to the way of entrance, which induces more than four times higher intracellular stability and indicates that the folate-mediated route of cell entry is more efficient than the nucleolin-mediated one when both folate and AS1411 modifications are present.

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42

Deller, Andrei E., Ana L. Soares, Jaqueline Volpe, Jean G. A. Ruthes, Dênio E. P. Souto, and Marcio Vidotti. "Development of Folate-Group Impedimetric Biosensor Based on Polypyrrole Nanotubes Decorated with Gold Nanoparticles." Biosensors 12, no. 11 (November 4, 2022): 970. http://dx.doi.org/10.3390/bios12110970.

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In this study, polypyrrole nanotubes (PPy-NT) and gold nanoparticles (AuNPs) were electrochemically synthesized to form a hybrid material and used as an electroactive layer for the attachment of proteins for the construction of a high-performance biosensor. Besides the enhancement of intrinsic conductivity of the PPy-NT, the AuNPs act as an anchor group for the formation of self-assembly monolayers (SAMs) from the gold–sulfur covalent interaction between gold and Mercaptopropionic acid (MPA). This material was used to evaluate the viability and performance of the platform developed for biosensing, and three different biological approaches were tested: first, the Avidin-HRP/Biotin couple and characterizations were made by using cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS), wherein we detected Biotin in a linear range of 100–900 fmol L−1. The studies continued with folate group biomolecules, using the folate receptor α (FR-α) as a bioreceptor. Tests with anti-FR antibody detection were performed, and the results obtained indicate a linear range of detection from 0.001 to 6.70 pmol L−1. The same FR-α receptor was used for Folic Acid detection, and the results showed a limit of detection of 0.030 nmol L−1 and a limit of quantification of 90 pmol L−1. The results indicate that the proposed biosensor is sensitive and capable of operating in a range of clinical interests.

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43

Ambrosio, Allison J., Daphne Suzin, Edwin L. Palmer, and Richard T. Penson. "Vintafolide (EC145) for the treatment of folate-receptor-α positive platinum-resistant ovarian cancer." Expert Review of Clinical Pharmacology 7, no. 4 (April 18, 2014): 443–50. http://dx.doi.org/10.1586/17512433.2014.909723.

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44

Mitra, AshimK, J. Renukuntla, S. Shah, S. H. S. Boddu, AD Vadlapudi, RK Vadlapatla, and D. Pal. "Functional characterization and expression of folate receptor-α in T47D human breast cancer cells." Drug Development and Therapeutics 6, no. 2 (2015): 52. http://dx.doi.org/10.4103/2394-6555.162441.

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45

He, Zhiyao, Yiyi Yu, Ying Zhang, Yongdong Yan, Yu Zheng, Jun He, Yongmei Xie, Gu He, Yuquan Wei, and Xiangrong Song. "Gene Delivery with Active Targeting to Ovarian Cancer Cells Mediated by Folate Receptor α." Journal of Biomedical Nanotechnology 9, no. 5 (May 1, 2013): 833–44. http://dx.doi.org/10.1166/jbn.2013.1587.

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46

Salem, Ragaa A., Nadia G. El-Hefnawy, Faten W. Ragheb, Iman H. Hewedi, Lobna S. Shash, and Dalia M. Ismail. "Folate receptor-α expression in triple-negative and non-triple-negative invasive breast carcinoma." Egyptian Journal of Pathology 37, no. 2 (December 2017): 268–73. http://dx.doi.org/10.1097/01.xej.0000526546.49017.77.

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47

Wu, Liping, Yue Liu, Rong Huang, Huawen Zhao, and Weiqun Shu. "Rapid and Selective Determination of Folate Receptor α with Sensitive Resonance Rayleigh Scattering Signal." International Journal of Analytical Chemistry 2017 (May 25, 2017): 1–6. http://dx.doi.org/10.1155/2017/1670812.

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A rapid, simple, and novel method for folate receptor α (FRα) determination is reported here. A probe of gold nanoparticles (Au NPs) modified with anti-FRα antibody was synthesized under the optimized conditions first. The antibody-modified Au NPs would aggregate when FRα was added to the probe for the specific interaction between antibody and antigen, resulting in the enhancement of resonance Rayleigh scattering (RRS) intensity. There is a linear relationship between the change of RRS intensity (ΔIRRS) and the concentration of FRα, with the detecting range of 0.50–37.50 ng·mL−1 and the limit of determination of 0.05 ng·mL−1. The determination of FRα in serum samples was realized with the advantages of high selectivity, high sensitivity, and easy operation.

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48

Chan, Stephen Y., Cyril J. Empig, Frank J. Welte, Roberto F. Speck, Alan Schmaljohn, Jason F. Kreisberg, and Mark A. Goldsmith. "Folate Receptor-α Is a Cofactor for Cellular Entry by Marburg and Ebola Viruses." Cell 106, no. 1 (July 2001): 117–26. http://dx.doi.org/10.1016/s0092-8674(01)00418-4.

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49

Henderson, Elisa A., Vassilios Bavetsias, Davinder S. Theti, Stuart C. Wilson, Rainer Clauss, and Ann L. Jackman. "Targeting the α-folate receptor with cyclopenta[g]quinazoline-based inhibitors of thymidylate synthase." Bioorganic & Medicinal Chemistry 14, no. 14 (July 15, 2006): 5020–42. http://dx.doi.org/10.1016/j.bmc.2006.03.001.

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50

Sivakumaran, Suneethi, Juan Zhang, Karen M. M. Kelley, Mesfin Gonit, Hong Hao, and Manohar Ratnam. "Androgen activation of the folate receptor α gene through partial tethering of the androgen receptor by C/EBPα." Journal of Steroid Biochemistry and Molecular Biology 122, no. 5 (November 2010): 333–40. http://dx.doi.org/10.1016/j.jsbmb.2010.08.008.

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