Progesterone and androgens are important for normal development and tumorigenesis of the breast.
Breast tissue samples from 49 premenopausal women were obtained. The progesterone receptors (PRA, PRB, ...PGRMC1 and PGRMC2) and the androgen receptor (AR) were determined in malignant and benign breast tumors and control tissues.
The PRB and AR mRNA levels were highest in tumors. PGRMC1 and PGRMC2 mRNA levels were higher in malignant tumors compared to their paired normal tissues. PRA protein showed most immunostaining in benign tumors. PRB immunostaining varied according to menstrual phase. AR immunostaining was highest in the glands of malignant tumors.
Progesterone and androgen receptors are differently regulated in tumors compared to normal breast tissues. A malignant breast tumor could appear PR-negative if collected in the luteal phase, but positive in the follicular phase. This finding may have clinical implications.
Estrogen hormones have a large impact on both normal development and tumorigenesis of the breast.
Breast tissue samples from 49 women undergoing surgery were included. The estrogen receptors (ERα and ...ERβ), ERα36 and G-coupled estrogen receptor-1 (GPER) were determined in benign and malignant breast tissue.
The ERα36 and ERα mRNA levels were highest in malignant tumors. Stromal ERβ immunostaining in benign tumors was higher than in the paired normal tissue. GPER expression was lowest in benign tumors. In the malignant tumors, the Nottingham Prognostic Index (NPI) correlated positively with stromal GPER and the serum testosterone level. The serum insulin-like growth factor-1 (IGF-1) level correlated negatively with GPER mRNA and glandular ERα.
The expression of ERα36 is stronger in malignant breast tissue. The strong positive correlation between NPI and GPER in malignant breast stroma indicates an important role for GPER in breast cancer prognosis.
Stromal factors have been identified as important for tumorigenesis and metastases of breast cancer. From 49 premenopausal women, samples were collected from benign or malignant tumors and the ...seemingly normal tissue adjacent to the tumor. The factors studied, with real-time polymerase chain reaction (PCR) and immunohistochemistry, were cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2), syndecan-1 (S-1) and connective tissue growth factor (CTGF).
COX-1 and S-1 mRNA levels were higher in the malignant tumors than in normal and benign tissues. The COX-2 mRNA level was lower in the malignant tumor than in the normal tissue, while CTGF mRNA did not differ between the groups.
COX-1 immunostaining was higher in stroma from malignant tumors than in benign tissues, whereas COX-2 immunostaining was higher in the malignant tissue. Glandular S-1 immunostaining was lower in malignant tumors compared to benign and normal tissues, and the opposite was found in stroma.
Conclusively, mRNA levels of COX-1 and COX-2 were oppositely regulated, with COX-1 being increased in the malignant tumor while COX-2 was decreased. S-1 protein localization switched from glandular to stromal cells in malignant tissues. Thus, these markers are, in premenopausal women, localized and regulated differently in normal/benign breast tissue as compared to the malignant tumor.
The Oslo Cyclotron Laboratory Görgen, A.; Guttormsen, M.; Larsen, A. C. ...
European physical journal plus,
02/2021, Letnik:
136, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Research at the Oslo Cyclotron Laboratory at the University of Oslo is focused on spectroscopy experiments for nuclear structure and nuclear astrophysics using the Oslo Scintillator Array OSCAR. ...Light-ion beams from the
K
=
35
cyclotron are furthermore used for studies in radiation biology and medical physics, for research and development related to medical isotope production, and for irradiation of materials and electronics components. Here we present an overview of the laboratory and its research infrastructure, give a brief discussion of the respective research programs and methods, and present recent highlights.
To elucidate if percutanous treatment with 10
mg testosterone per day could enhance sexuality and psychological well-being in postmenopausal women presenting problems with low libido. Secondary to ...study the influence on blood lipids, hemoglobin and erythropoietin levels.
Fifty-three postmenopausal women participated. As a complement to their already on-going HRT, 10
mg of a testosterone gel (Testogel, Besins–Iscovesco) or placebo was administered. Treatment continued for three plus three months in a double blind, randomized, crossover design.
The scores concerning “frequency of sexual activity, orgasm and intercourse”, “sexual arousal, fantasies and enjoyment”, “satisfaction with orgasms”, and “interest in sex” were all significally improved for testosterone addition as compared to placebo both before and after crossover. Testosterone levels increased more than 10-fold during treatment while DHT-levels were more than doubled. Estrogen levels were not affected during the addition of testosterone. Liver enzymes, total cholesterol, triglycerides, HDL and LDL revealed no significant differences between any of the periods or groups. Endometrial thickness did not change significantly during treatment. Hemoglobin and erythropoietin remained unchanged. No significant differences in the number of experienced side effects were found.
Testosterone gel of 10
mg had positive effects on several aspects of sexual life such as frequency of sexual activity, orgasm, arousal, fantasies and sexual interest in postmenopausal women on HRT. Several psychological variables were positively influenced. The given dose resulted in too high serum levels. Even if no negative effects were observed, monitoring of serum levels and a decreased dose should be considered in future studies.
The association between oral contraceptive (OC) use and breast cancer is not fully understood. Estrogen is a known mitogen to breast epithelial cells, but there is still a controversy about the ...effect of added progestogens. Fine needle aspiration (FNA) biopsies were used to assess epithelial proliferation in normal breast tissue from 106 healthy premenopausal women with and without oral contraceptives. In 26 women biopsies were performed before and after 2 months of OC use. Proliferation, expressed as percentage of Ki-67/MIB-1 positive cells, was correlated to endogenous progesterone, androgenic/anabolic compounds and exogenous progestogen. We found a higher proliferation (p = 0.03) in OC users compared to non users, with mean values of 4.8% and 2.2%, respectively. There was a positive correlation between proliferation and progesterone levels in non-users and with serum levonorgestrel concentrations in women using OCs containing this progestogen (rs = 0.43, p = 0.02). Women using OCs had significantly lower serum androgen levels compared to naturally cycling women and free testosterone levels displayed an inverse relation to breast epithelial proliferation. There was a marked variation in the response to exogenous sex steroids. In certain women after 2 months of OC use, the percentage of MIB-1 positive cells was as high as 40-50%. The results add to the growing evidence that progestogens may be mitogenic in breast tissue. Increased proliferation during hormonal contraception should be regarded as an unwanted and potentially hazardous side effect. Efforts should be made to define hormonal contraceptive regimens which minimize breast epithelial proliferation and to identify those women with the most pronounced proliferative response.
The mammary stroma is important for modulating epithelial breast cell response to sex steroid hormones. Proteoglycans, such as syndecan-1, promote the integration of cellular signals.
The ...immunohistochemical expression of syndecan-1 and of the androgen receptor (AR) was analyzed in paired samples of cancer and adjacent normal tissue from postmenopausal women.
Normal and cancer tissue showed dramatic differences in the expression of syndecan-1. In malignant breast stroma, mean values were more than 10-fold higher than in normal tissue (p<0.001). There was also a marked redistribution from the epithelium to the stroma. The expression of AR was on average 2-fold higher in cancerous than in normal tissue (p<0.01).
Breast cancer patients have very different prognoses. Syndecan-1 and the AR may be new molecular markers relevant to clinical outcome. The redistribution from the epithelium and the dramatic increase of syndecan-1 in cancerous stroma may be related to the natural history of the disease.
The α-particle emitting radionuclides
223Ra (t
1
2
= 11.4 d),
224Ra (t
1
2
= 3.6 d), and
225Ac(t
1
2
= 10.0 d) may have a broad application in targeted radiotherapy provided that they could be linked ...to vehicles with tumor affinity. The potential usefulness of liposomes as carriers was studied in the present work. Radium and actinium radionuclides could be loaded in good yields into sterically stabilized lipsomes. Subsequent coating of the lipsomes with a folate-F(ab′)
2 construct yielded a product with affinity towards tumor cells expressing folate receptors. Radionuclide loaded liposomes showed excellent stability in serum in vitro.
Intracranial (IC) locoregional delivery of chimeric antigen receptor (CAR) T cells presents an attractive delivery method to central nervous system tumors. Although IC delivery is actively being ...employed in early-phase clinical studies, no thaw/wash methods have been published to remove the neurotoxic cryoprotectant dimethyl sulfoxide (DMSO) from CAR T-cell products before IC administration. Thus, the aim of this study was to develop and validate a simple thaw/wash procedure.
We developed a thaw/wash procedure that consist of product thaw at 37°C, equilibration for 5 min in 1 volume of preservative-free normal saline (PFNS), dilution with an additional 8 volumes of PFNS, removal of DMSO through a washing step, resuspension in 2.0 mL of PFNS and storage in a syringe at 20-25°C. Final formulated products (FPs) were assessed for quality and safety attributes and stability over 3 h from the completion of the thaw. Stability parameters included CAR T-cell viability, transgene surface expression and cytolytic activity.
The developed procedure reduced the calculated % of DMSO to less than 0.025%. FP cell viability and recovery (versus pre-cryopreservation) were within acceptable specifications (mean viability: 85.3%, range: 83%-88%; total nucleated cell recovery mean: 76.5%, range: 65.4%-82.5%). Other prespecified quality assurance/quality control parameters including appearance/ integrity, sterility and endotoxin level (≤1.0 EU/mL), were also met by all FPs (n = 3). Three hours' post thaw/wash stability was confirmed. All products maintained cell viability greater than 70% (mean, 80.0%; range, 79%-81%), with no significant change in transgene expression or cytolytic activity of B7-H3-CAR T cells compared with thawed not diluted/washed control CAR T cells.
We have developed a simple thaw/wash procedure to prepare B7-H3-CAR T cells for their locoregional delivery to the neural axis. While we focus here on CAR T cells, the methods could be readily adapted to other cryopreserved immune effector cell products.
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