Neurotensin (NTS) is a peptide discovered in 1973, which has been studied in many fields and mainly in oncology for its action in tumor growth and proliferation. In this review of the literature, we ...wanted to focus on its involvement in reproductive functions. NTS participates in an autocrine manner in the mechanisms of ovulation via NTS receptor 3 (NTSR3), present in granulosa cells. Spermatozoa express only its receptors, whereas in the female reproductive system (endometrial and tube epithelia and granulosa cells), we find both NTS secretion and the expression of its receptors. It consistently enhances the acrosome reaction of spermatozoa in mammals in a paracrine manner via its interaction with NTSR1 and NTSR2. Furthermore, previous results on embryonic quality and development are discordant. NTS appears to be involved in the key stages of fertilization and could improve the results of in vitro fertilization, especially through its effect on the acrosomal reaction.
Meningiomas are, in most cases, low grade intracranial tumors. However, relapses are frequent. To date, only a few prognostic markers are described in the literature. Several studies have discussed ...the expression of progesterone, estrogen, androgen, and somatostatin receptors. The utility of analyzing these expressions for prognostic, theragnostic, and therapeutic purposes remains unclear. The aim of this study was to report the expression of these receptors, based on immunohistochemistry. Cochrane Collaboration guidelines and PRISMA statements were followed. We did an online search in PubMed using the MeSH database. References were selected if the investigations occurred from 1990 to 2022. 61 references were included (34 descriptive observational studies, 26 analytical observational studies, and one case report). In this review, we describe the expression of these receptors in function of age, sex, hormonal context, localization, histological subtype, grade, and recurrence.
The high affinity receptor 1 (NTSR1) and its agonist, neurotensin (NTS), are correlated with tumor cell aggressiveness in most solid tumors. As chemoresistance and tumor aggressiveness are often ...related, we decided to study the role of the NTSR1 complex within platinum-based chemotherapy responses. In an ovarian model, we studied carboplatin because it is the main standard of care for ovarian cancer.
Experimental tumors and
studies were performed using SKOV3 and A2780 cells treated with carboplatin, with or without a very specific NTSR1 antagonist, SR48692. We measured the effects of these treatments on cell apoptosis and apoptosis-related proteins, platinum accumulation in the cell and nucleus, and the expression and localization of platinum transporters. NTS and NTSR1 labeling was measured in patients with ovarian cancer.
SR48692 enhanced the response to carboplatin in ovarian cancer cells and experimental tumors. When SR48692 is combined with carboplatin, we noted a major improvement of platinum-induced DNA damage and cell death, as well as a decrease in tumor growth. The relationship of these results to clinical studies was made by the detection of NTS and NTSR1 in 72% and 74% of ovarian cancer, respectively. Furthermore, in a large series of high-grade ovarian cancer, NTSR1 mRNA was shown to correlate with higher stages and platinum resistance.
This study strongly suggests that the addition of NTSR1 inhibitor in combination with platinum salt-based therapy will improve the response to the drug.
.
Current histoprognostic parameters and prognostic scores used in paragangliomas and pheochromocytomas do not adequately predict the risk of metastastic progression and survival. Here, using a series ...of 147 cases of paraganglioma and pheochromocytoma, we designed and evaluated the potential of a new score, the COPPS (COmposite Pheochromocytoma/paraganglioma Prognostic Score), by taking into consideration three clinico-pathological features (including tumor size, necrosis, and vascular invasion), and the losses of PS100 and SDHB immunostain to predict the risk of metastasis. We compared also the performance of the COPPS with several presently used histoprognostic parameters in risk assessment of these tumors. A PASS score (Pheochromocytoma of the Adrenal gland Scaled Score) ≥ 6 was significantly associated with the occurrence of metastases (
P
< 0.0001) and shorter PFS (
P
= 0.013). In addition, both MCM6 and Ki-67 LI correlated with worse PFS (
P
= 0.004 and
P
< 0.0001, respectively), and MCM6, but not Ki-67, was significantly higher in metastatic group (
P
= 0.0004). Loss of PS100 staining correlated with the occurrence of metastasis (
P
< 0.0001) and shorter PFS (
P
< 0.0001). At a value of greater or equal to 3, the COPPS correlated with shorter PFS (
P
< 0.0001), and predicted reproducibly (weighted Kappa coefficient, 0.863) the occurrence of metastases with a sensitivity of 100.0% and specificity of 94.7%. It thus surpassed those found for either PASS, SDHB, MCM6, or Ki-67 alone. In conclusion, while validation is still necessary in independent confirmatory cohorts, COPPS could be of great potential for the risk assessment of metastasis and progression in paragangliomas and pheochromocytomas.
HuR regulates cytoplasmic mRNA stability and translatability, with its expression correlating with adverse outcomes in various cancers. This study aimed to assess the prognostic value and ...pro-oncogenic properties of HuR and its post-translational isoforms methyl-HuR and phospho-HuR in endometrial adenocarcinoma. Examining 89 endometrioid adenocarcinomas, we analyzed the relationship between HuR nuclear or cytoplasmic immunostaining, tumor-cell proliferation, and patient survival. HuR cytoplasmic expression was significantly increased in grade 3 vs. grade 1 adenocarcinomas (
< 0.001), correlating with worse overall survival (OS) (
= 0.02). Methyl-HuR cytoplasmic expression significantly decreased in grade 3 vs. grade 1 adenocarcinomas (
< 0.001) and correlated with better OS (
= 0.002). Phospho-HuR nuclear expression significantly decreased in grade 3 vs. grade 1 adenocarcinomas (
< 0.001) and non-significantly correlated with increased OS (
= 0.06). Cytoplasmic HuR expression strongly correlated with proliferation markers MCM6 (rho = 0.59 and
< 0.001) and Ki67 (rho = 0.49 and
< 0.001). Conversely, these latter inversely correlated with cytoplasmic methyl-HuR and nuclear phospho-HuR. Cytoplasmic HuR expression is a poor prognosis marker in endometrioid endometrial adenocarcinoma, while cytoplasmic methyl-HuR and nuclear phosphoHuR expressions are markers of better prognosis. This study highlights HuR as a promising potential therapeutic target, especially in treatment-resistant tumors, though further research is needed to understand the mechanisms regulating HuR subcellular localization and post-translational modifications.
Overall survival of patients with metastatic non-small cell lung cancer (NSCLC) has significantly improved with platinum-based salt treatments and recently with targeted therapies and ...immunotherapies. However, treatment failure occurs due to acquired or emerging tumor resistance.
We developed a monoclonal antibody against the proform of neurotensin (LF-NTS mAb) that alters the homeostasis of tumors overexpressing NTSR1. Neurotensin is frequently overexpressed along with its high affinity receptor (NTSR1) in tumors from epithelial origins. This ligand/receptor complex contributes to the progression of many tumor types by activation of the cellular effects involved in tumor progression (proliferation, survival, migration, and invasion).
We demonstrate that LF-NTS mAb operates on the plasticity of tumor cells overexpressing NTSR1 and lowers their aggressiveness. The mAb enables the restoration of platinum-based therapies responsiveness, while also decreasing metastatic processes. Efficacy dosage with long-term treatment showed no obvious adverse events, while demonstrating improvement in the performance status. Our data suggests that LF-NTS mAb is an ideal candidate to be safely added to the conventional standard of care in order to improve its efficacy.
•Neurotensin targeted therapy decreases tumor growth and metastasis processes, while restoring drug responsiveness.•Neurotensin targeted therapy creates no additional toxicity.•Neurotensin targeted therapy improves performance status.
Minichromosome maintenance complex component 6 (MCM6) is involved in initiating DNA replication and is upregulated during licensed G0 phase of the cell cycle. This early expression permits its ...labeling of more proliferating cells than those by Ki-67. Here using a cohort of 89 endometrioid adenocarcinoma, we report findings made on the prognostic value of MCM6 based on immunohistochemical labeling index (LI) of the protein in comparison with that of Ki67 as no such information is currently available. Additionally, we examined the prognostic values of these markers based on their mRNA expression using a cohort of uterine corpus endometrial carcinoma (UCEC,
n
= 307) taken from The Cancer Genome Atlas (TCGA) database. Our evidence indicated the presence of a positive correlation between the LI of MCM6 and the histological grade of endometrioid endometrial adenocarcinoma (grade I, 66.7%; grade II, 75.3%; grade III, 81.4%;
p
< 0.001) and an inverse correlation between the LI of MCM6 and the overall and progression-free survival (
p =
0.02 for both). The LI of Ki-67 correlated with grade (
p
< 0.001), but not survival. The MCM6 and Ki-67 inter-observer intra-class correlation coefficients were excellent: 0.84 (95% confidence interval, 0.83–0.91) and 0.84 (0.77–0.90), respectively. For in silico analyses of the TCGA cohort, both univariate and multivariate Cox analyses (
p =
0.003 and
p
= 0.03, respectively) revealed high MCM6 mRNA
Z
-scores associated with reduced overall survival. This association was absent for Ki-67. MCM6 is thus a highly reproducible marker of poor prognosis in endometrial cancer. Evaluation of MCM6 should thus be considered in daily practice for risk stratification.
The molecular basis of McCune Albright syndrome (MAS) is a recurrent GNAS Postzygotic gain of function sporadic mutation, resulting in a mosaic disease. Most of girls present precocious puberty, ...caused by the development of recurrent ovarian cysts with autonomous Hyperestrogenic stimulation. After menarche, the majority of patients with ovarian GNAS mutation have menstrual disturbances and infertility.
We wanted to focus on the fertility of MAS females and propose an appropriate management, by a detailed case report and an exhaustive review of the literature on fertility and pregnancy in MAS females.
We present the case of a 29-year-old MAS female, who had previously undergone a unilateral ovariectomy and was managed by in vitro fertilization (IVF). Eight oocytes with many morphological abnormalities were retrieved. The GNAS mutation was found at a low frequency in follicular cells. The ovarian histopathological examination showed developing follicles of all stages, strongly expressing AMH by immunohistochemistry. In addition, AMH was high (45.5 pmol/L) and the AMH / AFC ratio (5.69 pmol/L per follicle) was much higher than in PCOS and control groups (2.16, and 1.34 respectively).
Ovarian and endometrial involvement can be responsible for infertility in MAS women. IVF and oophorectomy may be useful in management. The genetic characterization of the different tissues may have a prognostic utility. Moreover, we suggest that the AMH could be a marker of the ovarian activity in MAS. Further studies are needed to clarify the potential oocyte abnormalities and the risk of miscarriages in order to guide genetic counseling.
The promalignant effects of neurotensin (NTS) are sustained in many solid tumors, including hormone-dependent cancers. As the endometrium is also subjected to hormonal regulation, we evaluated the ...contribution of NTS to endometrial carcinogenesis. Neurotensin receptor 1 (NTSR1) expression and
NTSR1
promoter methylation (HM450) were analyzed in 385 cases of endometrial carcinoma from The Cancer Genome Atlas (TCGA). Additionally, from a series of 100 endometrial carcinomas, and 66 benign endometrium samples, NTS and NTSR1 labeling was evaluated by immunohistochemistry. Using TCGA series, NTSR1 messenger RNA (mRNA) level was negatively correlated with overall survival (OS) and progression-free survival (PFS) (
p
= 0.0012 and
p
= 0.0116, respectively), and positively correlated with the grade (
p
= 0.0008). When including only endometrioid carcinomas, NTSR1 mRNA level continued to be negatively correlated with OS (log-rank:
p
< 0.0001) and PFS (log-rank:
p
= 0.002). A higher NTSR1 mRNA level was significantly associated with a loss of NTSR1 promoter methylation. Immunohistochemical expression of NTS and NTSR1 was significantly increased in adenocarcinoma (
n
= 100), as compared to benign endometrium (
p
< 0.001). NTSR1 expression was positively correlated with grade (
p
= 0.004). High immunohistochemical expression of cytoplasmic NTSR1 was significantly correlated with a shorter OS and PFS (
p
< 0.001 and
p
= 0.001, respectively). This correlation remained significant when excluding non-endometrioid subtypes (
p
= 0.04 and
p
= 0.02, respectively). In multivariate analysis, the expression of NTSR1 was an independent prognostic factor (
p
= 0.004). NTSR1 overexpression is a poor prognostic factor in endometrial cancer, highlighting the contribution of NTS in endometrial cancer progression and its uses as a prognostic marker, and as a potential therapeutic target.
Abstract The better knowledge of the mechanisms of nuclear incidents and lessons learned from accidents in the recent past to improve the effectiveness of measures taken following a nuclear accident ...exposure to fallout of radioactive iodine isotopes. Thus, immediate, passive measures, such as containment, and stopping consumption of contaminated products are paramount. The earliest possible administration of stable iodine as potassium iodide (KI) reduces significantly (up to 90% if taken at the same time of the accident) thyroid radioactive contamination. These tablets should be given in priority to children and pregnant women. The side effects are minor. KI is not recommended for persons aged over 60 years, or for adults suffering from cardiovascular disorders.
PDF
