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1.
Eur J Surg Oncol ; 43(7): 1258-1264, 2017 Jul.
Article in English | MEDLINE | ID: mdl-28214052

ABSTRACT

AIMS: Tumor-infiltrating FoxP3+ T cells and FoxP3+ tumor cells have been reported in breast cancer (BC), which impaired immunity and promoted tumors progression. However, their prognostic value for survival in patients with breast BC remains controversial. METHODS: A meta-analysis was performed. Original data included the hazard ratios (HR) of overall survival (OS), relapse-free survival and odds ratio (OR) in BC patients. We pooled HR/OR with 95% confidence intervals (CI) to estimate the hazard. RESULTS: The overall survival of high tumor-infiltrating FoxP3+ T cells patients was lower than low tumor-infiltrating FoxP3+ T cells patients with estrogen receptor (ER)-positive (HR 0.86, 95% CI 0.77-0.96; P = 0.009) but not ER-negative (HR 1.09, 95% CI 0.82-1.45; P = 0.569) BC. And FoxP3+ tumor cells were not associated with the overall survival and recurrences of BC patients (P > 0.05). In addition, a significant association was revealed between high tumor-infiltrating FoxP3+ T cells and grade (I + II/III: OR 0.31, 95% CI 0.17-0.56; P < 0.001), ER status (present: OR 2.39, 95% CI 1.51-3.76; P < 0.001), HER2 status (present: OR 0.53, 95% CI 0.36-0.78; P = 0.001), PR status (present: OR 1.88, 95% CI 1.31-2.71; P < 0.001). And a significant association was revealed between positive FoxP3+ tumor cells and Nodal status (present: OR 0.48, 95% CI 0.23-0.97; P = 0.04), grade (I + II/III: OR 0.44, 95% CI 0.22-0.85; P = 0.01), PR status (present: OR 2.37, 95% CI 1.54-3.36; P < 0.001). CONCLUSIONS: High tumor-infiltrating FoxP3+ T cells were associated with a poorer prognosis for ER-positive BC, but not for ER-negative BC.


Subject(s)
Breast Neoplasms/chemistry , Breast Neoplasms/immunology , Forkhead Transcription Factors/analysis , Lymphocytes, Tumor-Infiltrating/chemistry , Receptors, Estrogen/analysis , T-Lymphocytes/chemistry , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Disease-Free Survival , Female , Humans , Lymphatic Metastasis , Lymphocytes, Tumor-Infiltrating/immunology , Receptor, ErbB-2/analysis , Receptors, Progesterone/analysis , Survival Rate , T-Lymphocytes/immunology
2.
Cell Death Dis ; 5: e1148, 2014 Mar 27.
Article in English | MEDLINE | ID: mdl-24675466

ABSTRACT

Familial neurohypophysial diabetes insipidus (FNDI) characterized by progressive polyuria is mostly caused by mutations in the gene encoding neurophysin II (NPII), which is the carrier protein of the antidiuretic hormone, arginine vasopressin (AVP). Although accumulation of mutant NPII in the endoplasmic reticulum (ER) could be toxic for AVP neurons, the precise mechanisms of cell death of AVP neurons, reported in autopsy studies, remain unclear. Here, we subjected FNDI model mice to intermittent water deprivation (WD) in order to promote the phenotypes. Electron microscopic analyses demonstrated that, while aggregates are confined to a certain compartment of the ER in the AVP neurons of FNDI mice with water access ad libitum, they were scattered throughout the dilated ER lumen in the FNDI mice subjected to WD for 4 weeks. It is also demonstrated that phagophores, the autophagosome precursors, emerged in the vicinity of aggregates and engulfed the ER containing scattered aggregates. Immunohistochemical analyses revealed that expression of p62, an adapter protein between ubiquitin and autophagosome, was elicited on autophagosomal membranes in the AVP neurons, suggesting selective autophagy induction at this time point. Treatment of hypothalamic explants of green fluorescent protein (GFP)-microtubule-associated protein 1 light chain 3 (LC3) transgenic mice with an ER stressor thapsigargin increased the number of GFP-LC3 puncta, suggesting that ER stress could induce autophagosome formation in the hypothalamus of wild-type mice as well. The cytoplasm of AVP neurons in FNDI mice was occupied with vacuoles in the mice subjected to WD for 12 weeks, when 30-40% of AVP neurons are lost. Our data thus demonstrated that autophagy was induced in the AVP neurons subjected to ER stress in FNDI mice. Although autophagy should primarily be protective for neurons, it is suggested that the organelles including ER were lost over time through autophagy, leading to autophagy-associated cell death of AVP neurons.


Subject(s)
Arginine Vasopressin/metabolism , Autophagy , Diabetes Insipidus, Neurogenic/metabolism , Diabetes Insipidus, Neurogenic/pathology , Neurons/metabolism , Neurons/pathology , Adaptor Proteins, Signal Transducing/metabolism , Animals , Disease Models, Animal , Endoplasmic Reticulum/metabolism , Endoplasmic Reticulum/ultrastructure , Endoplasmic Reticulum Stress , Heat-Shock Proteins/metabolism , Hypothalamus/metabolism , Hypothalamus/pathology , Inclusion Bodies/metabolism , Inclusion Bodies/ultrastructure , Mice , Models, Biological , Neurons/ultrastructure , Phagosomes/metabolism , Phagosomes/ultrastructure , Phenotype , Protein Aggregates , Sequestosome-1 Protein , Ubiquitinated Proteins/metabolism , Water Deprivation
4.
Cancer Immunol Immunother ; 44(6): 323-8, 1997 Aug.
Article in English | MEDLINE | ID: mdl-9298934

ABSTRACT

A comparison was made between the murine anti-MUC1 antibody BC2 (which reacts with the peptide epitope APDTR) and the "humanised" antibody hCTMO1 from CellTech, which reacts with the MUC1 epitope RPAP. Preliminary studies demonstrated that hCTMO1 was a "good" antibody whereas BC2 was not. Various parameters were determined and conclusions reached. (a) Affinity: the affinity of hCTMO1 was 2.60 x 10(7) M(-1) and that of BC2 was 1.36 x 10(7) M(-1); we did not consider these numbers to be substantially different, although hCTMO1 was clearly of higher affinity than BC2. (b) On/off rate at 4 degrees C: both antibodies bound effectively to the MUC-1 transfectant MOR5-CF2; the association rate for hCTMO1 was 3.8 times that of BC2 and the dissociation rate for BC2 was twice as fast as that of hCTMO1. (c) On/off rates at 37 degrees C: at 37 degrees C the association rate for hCTMO1 was greater than that of BC2. (d) Internalization: hCTMO1 was also more efficient at internalising bound antibody; 70% of bound hCTMO1 was internalised, whilst 6% of bound BC2 was internalised. From these studies it was clear that, while hCTMO1 was of similar affinity to BC2, the faster uptake and internalisation and lower off rate indicated that it was likely to be a superior antibody; this was proven in vivo. (e) Localisation: hCTMO1 bound much better in vivo than BC2 (68% compared to 28%). (f) Therapeutic experiments: BC2-idarubicin conjugates were essentially ineffective in eradicating tumours in mice whereas hCTMO1-idarubicin had a dramatic effect on breast cancer tumour cells growing in mice. We conclude that the simple measurements on/off rates and internalisation at 37 degrees C are the most important parameters to use to determine antibody effectiveness, prior to embarking on clinical studies.


Subject(s)
Antibodies, Monoclonal/metabolism , Antibodies, Monoclonal/pharmacology , Mucin-1/immunology , 3T3 Cells , Animals , Antigens/metabolism , Epitopes/metabolism , Image Processing, Computer-Assisted , Iodine Radioisotopes , Kinetics , Mice , Mice, Inbred BALB C , Temperature , Tissue Distribution
5.
Cancer Immunol Immunother ; 41(1): 53-60, 1995 Jul.
Article in English | MEDLINE | ID: mdl-7543822

ABSTRACT

Mouse monoclonal antibodies to CD19 detect an antigenic determinant expressed exclusively on the surface of B lymphocytes, and have previously been shown to be potentially useful therapeutic reagents for human B cell lymphoma. We report the production and characterization of a mouse/human chimeric antibody, cCD19, with potent in vivo antitumour activity. The genes encoding the variable domains for heavy (VH) and light (VL) chains were subcloned into eukaryotic expression vectors containing human constant region genes (IgG1 and kappa), and co-transfected into non-secreting Sp2/0 mouse myeloma cells. Intraperitoneal administration of cCD19 produced inhibition of growth of subcutaneous CD19+ Sultan human B lymphoma tumours in scid/scid mice. When the antibody was administered 18 and 20 days after subcutaneous tumour inoculation, an approximately 30% reduction in tumour size was noted by day 29. cCD19 faithfully mimicked the in vitro binding characteristics of mCD19 as (a) the chimeric antibody was shown by flow cytometry to bind exclusively to cell lines that expressed CD19, (b) cCD19 was able to inhibit the binding of mCD19 on CD19+ cells completely and (c) the affinity of binding of the two antibodies was not significantly different [Ka = (2.03 +/- 1.5) x 10(8)]. In bio-distribution studies, up to 14.8% of the total injected antibody dose per gram of tissue was localized in CD19+ Sultan tumours at 24 h approximately, 14.4% was present in the tumors at 48 h, and about 13.7% at 72 h. These levels were comparable to mCD19 administered in the same fashion. cCD19 conjugated to idarubicin was specifically and strongly cytotoxic to CD19+ cells cultured in vitro, and demonstrated an IC50 of 0.17 microM, similar to that of mCD19 (0.32 microM) and approximately 14-fold greater than the IC50 of free idarubicin. The specific cytotoxic capacity of cCD19 and its likely reduced immunogenicity suggest that it may potentially be of use in the treatment of refractory B cell lymphoma in humans.


Subject(s)
Antibodies, Monoclonal/immunology , Antigens, CD/immunology , Antigens, Differentiation, B-Lymphocyte/immunology , B-Lymphocytes/immunology , Animals , Antigen-Antibody Reactions , Antigens, CD19 , Humans , Idarubicin/administration & dosage , Immunity, Cellular , Immunoconjugates/administration & dosage , Mice , Mice, SCID , Recombinant Fusion Proteins , Tumor Cells, Cultured/immunology
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