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1.
Clin Immunol ; 260: 109902, 2024 03.
Article in English | MEDLINE | ID: mdl-38218210

ABSTRACT

The devastating impact of COVID-19 on global health shows the need to increase our pandemic preparedness. Recombinant therapeutic antibodies were successfully used to treat and protect at-risk patients from COVID-19. However, the currently circulating Omicron subvariants of SARS-CoV-2 are largely resistant to therapeutic antibodies, and novel approaches to generate broadly neutralizing antibodies are urgently needed. Here, we describe a tetravalent bispecific antibody, A7A9 TVB, which actively neutralized many SARS-CoV-2 variants of concern, including early Omicron subvariants. Interestingly, A7A9 TVB neutralized more variants at lower concentration as compared to the combination of its parental monoclonal antibodies, A7K and A9L. A7A9 also reduced the viral load of authentic Omicron BA.1 virus in infected pseudostratified primary human nasal epithelial cells. Overall, A7A9 displayed the characteristics of a potent broadly neutralizing antibody, which may be suitable for prophylactic and therapeutic applications in the clinics, thus highlighting the usefulness of an effective antibody-designing approach.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Antibodies, Monoclonal/therapeutic use , Parents , Antibodies, Viral/therapeutic use , Antibodies, Neutralizing/therapeutic use
2.
FASEB J ; 34(2): 2812-2820, 2020 02.
Article in English | MEDLINE | ID: mdl-31908056

ABSTRACT

The Mre11A/RAD50/NBN complex (MRN) is an essential regulator of the cellular damage response after DNA double-strand breaks (DSBs). More recent work has indicated that MRN may also impact on the duration of mitosis. We show here that RAD50-deficient fibroblasts exhibit a marked delay in mitotic progression that can be rescued by lentiviral transduction of RAD50. The delay was observed throughout all mitotic phases in live cell imaging using GFP-labeled H2B as a fluorescent marker. In complementation assays with RAD50 phosphorylation mutants, modifications at Ser635 had little effect on mitotic progression. By contrast with RAD50, fibroblast strains deficient in ATM or NBN did not show a significant slowing of mitotic progression. Ataxia-telangiectasia-like disorder (ATLD) fibroblasts with nuclease-deficient MRE11A (p.W210C) tended to show slower mitosis, though by far not as significant as RAD50-deficient cells. Inhibitor studies indicated that ATM kinase activity might not grossly impact on mitotic progression, while treatment with MRE11A inhibitor PFM39 modestly prolonged mitosis. Inhibition of ATR kinase significantly prolonged mitosis but this effect was mostly independent of RAD50 status. Taken together, our data unravel a mitotic role of RAD50 that can be separated from its known functions in DNA repair.


Subject(s)
Acid Anhydride Hydrolases/metabolism , DNA Repair/physiology , DNA-Binding Proteins/metabolism , MRE11 Homologue Protein/genetics , Mitosis , Ataxia Telangiectasia/genetics , DNA Breaks, Double-Stranded , Humans
3.
BMC Cancer ; 18(1): 274, 2018 03 09.
Article in English | MEDLINE | ID: mdl-29523126

ABSTRACT

BACKGROUND: MYC overexpression is associated with poor prognosis in breast tumors (BCa). The objective of this study was to determine the prevalence of MYC amplification and associated markers in BCa tumors from African American (AA) women and determine the associations between MYC amplification and clinico-pathological characteristics. METHODS: We analyzed 70 cases of well characterized archival breast ductal carcinoma specimens from AA women for MYC oncogene amplification. Utilizing immune histochemical analysis estrogen receptor (ER), progesterone receptor (PR), and (HER2/neu), were assessed. Cases were Luminal A (ER or PR+, Ki-67 < 14%), Luminal B (ER or PR+, Ki-67 = > 14% or ER or PR+ HER2+), HER2 (ER-, PR-, HER2+), and Triple Negative (ER-, PR-, HER2-) with basal-like phenotype. The relationship between MYC amplification and prognostic clinico-pathological characteristics was determined using chi square and logistic regression modeling. RESULTS: Sixty-five (97%) of the tumors showed MYC gene amplification (MYC: CEP8 > 1). Statistically significant associations were found between MYC amplification and HER2-amplified BCa, and Luminal B subtypes of BCa (p < 0.0001), stage (p < 0.001), metastasis (p < 0.001), and positive lymph node status (p = 0.039). MYC amplification was associated with HER2 status (p = 0.01) and tumor size (p = 0.01). High MYC amplification was seen in grade III carcinomas (MYC: CEP8 = 2.42), pre-menopausal women (MYC: CEP8 = 2.49), PR-negative status (MYC: CEP8 = 2.42), and ER-positive status (MYC: CEP8 = 2.4). CONCLUSIONS: HER2 positive BCas in AA women are likely to exhibit MYC amplification. High amplification ratios suggest that MYC drives HER2 amplification, especially in HER2 positive, Luminal B, and subtypes of BCa.


Subject(s)
Black or African American/genetics , Breast Neoplasms/genetics , Gene Amplification , Proto-Oncogene Proteins c-myc/genetics , Receptor, ErbB-2/genetics , Receptors, Estrogen/genetics , Receptors, Progesterone/genetics , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/genetics , Carcinoma, Ductal, Breast/metabolism , Carcinoma, Ductal, Breast/pathology , Female , Follow-Up Studies , Humans , Middle Aged , Prognosis , Receptor, ErbB-2/metabolism , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Retrospective Studies
4.
Haematologica ; 88(11): 1253-8, 2003 Nov.
Article in English | MEDLINE | ID: mdl-14607754

ABSTRACT

BACKGROUND AND OBJECTIVES: Early treatment response is a strong predictor for treatment outcome in childhood acute lymphoblastic leukemia (ALL), treated within the protocols of the Berlin-Frankfurt-Münster (BFM) study group. In the ALL-BFM trials, early treatment response is assessed by in vivo response to glucocorticoids (prednisone response), the molecular background of which is unknown. Initial in vivo resistance to glucocorticoid (GC) treatment in childhood ALL (prednisone-poor response) is associated with a dramatically shorter event-free survival than that found in GC-sensitive patients (prednisone-good responders). The intracellular effects of glucocorticoids are mediated by the glucocorticoid receptor (GR). The protein expression of the GR has been linked to in vivo and in vitro GC resistance in various diseases treated with GC. However, existing data are conflicting. DESIGN AND METHODS: We performed a case-control study for prednisone response to investigate the association of in vivo GC resistance and GR protein expression in childhood ALL. GR expression was assessed using Western blot technology. RESULTS: The median relative GR protein expression of all patients was 0.87. Overall, we did not find different GR protein expression in PPR and PGR patients. GR protein expression was 0.91 in PGR patients versus 0.85 in PPR ones of in vivo GC resistance and GR expression. INTERPRETATION AND CONCLUSIONS: We conclude that the expression of GR is of minor importance for in vivo GC resistance in childhood ALL.


Subject(s)
Gene Expression Regulation, Leukemic , Neoplasm Proteins/biosynthesis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Receptors, Glucocorticoid/biosynthesis , Adolescent , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Asparaginase/administration & dosage , Case-Control Studies , Child , Child, Preschool , Cyclophosphamide/administration & dosage , Cytarabine/administration & dosage , Daunorubicin/administration & dosage , Disease-Free Survival , Drug Resistance, Neoplasm/genetics , Female , Humans , Male , Mercaptopurine/administration & dosage , Methotrexate/administration & dosage , Neoplasm Proteins/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Prednisone/administration & dosage , Protein Isoforms/biosynthesis , Protein Isoforms/genetics , Receptors, Glucocorticoid/genetics , Treatment Outcome , Vincristine/administration & dosage
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