Cervical cancer (CC), the second most common in developing countries and the third most common in developed nations, is the fourth most common type of cancer in women overall. The HPV16 high-risk genotype of the virus, which is responsible for about 61% of cervical cancer incidences, was found to have higher LCN2 levels in advanced clinical CC stages. In this study, we assessed the impact of suppressing LCN2 activity after treatment with an anti-LCN2 monoclonal antibody (MAb) in both in vitro and in vivo settings. Anti-LCN2 antibody was found to reduce proliferation and invasion of HeLa cells, the first immortal cells from a HPV positive aggressive adenocarcinoma of the cervix. LCN2 and its ligand MMP9 was found to be highly expressed in the cells and abrogated on treatment with anti-LCN2. The five receptors of LCN2 - SLC22A17, MC1R, MC2R, MC4R and LRP2 were barely detected with or without treatment. Anti-LCN2 Mab caused tumors to regress and soften in vivo, in a xenograft mouse model. Analysis of histology images of the treated and untreated tumor established the necrotic capability of the therapeutic molecule explaining the regression and softening of the tumor. Differential gene expression analysis between untreated and treated tumor proved that LCN2 inhibition abolished the migratory, invasive, and hypoxic pathways while significantly increasing the necrosis and cell death pathways in tumor after treatment with the monoclonal antibody. LCN2 inhibition was shown molecularly to lead to tumor regression via a negative feedback loop of LCN2 through the TNFα-IL17 axis exponentially increasing the effect of the anti-LCN2 monoclonal antibody. In conclusion, LCN2 appears to be a viable therapeutic target, and the monoclonal antibody used in this study can be further developed for clinical usage in cervical cancer.
Introduction: Stress activates hypothalamo-pituitary-adrenal axis leading to the release of glucocorticoid that mediates the stress response. This adaptive response is self-limited but if persistent for prolonged periods can lead to disease states. Nature has endowed the body with efficient buffer systems to attenuate the stress effects and Dehydroepiandrosterone (DHEA), a steroid hormone with neuromodulatory functions is implicated as an efficient candidate to buffer stress. Aim: To assess the effect of prophylactic administration of DHEA in the attenuation of acute stress in male Wistar rats. Materials and Methods: This interventional study was carried out at centre for Toxicology and Developmental Research, Sri Ramachandra Institute of Higher Education and Research, Chennai, between June 2021 and August 2021, in compliance with the animal welfare guidelines of CPCSEA, and in accordance to the protocol approved by Institutional animal ethics committee. The 18 male Wistar rats approved for the study were segregated into 3 groups with 6 animals in control (no stress) group, 6 in stress group and 6 in intervention group that received DHEA prophylactically 30 min before stress procedure. Animals in stress and intervention groups were subjected to one hour immobilisation stress. Blood samples were collected from all animals after the stress period and serum corticosterone, the stress marker, was estimated. The data were expressed as mean±standard error of mean (mean±SEM) and Mann-Whitney U test was used to test the significant difference between the: (i) control & stress groups; (ii) stress & study groups; and (iii) control & study groups. The p-value<0.05 was considered significant. The analysis was done using SPSS version 23.0. Results: The values of corticosterone in control, stress and intervention groups were 26.6±4.4 ng/mL, 51.6±3.9 ng/mL and 23.4±3.6 ng/mL, respectively. Significant difference in the mean serum corticosterone levels with p-value 0.013 between control and stress groups and with p-value 0.008 between stress and DHEA groups were observed. Conclusion: It could be observed from the findings that prophylactic DHEA administration attenuated acute stress efficiently in male Wistar rats as reflected by the significant decrease in serum corticosterone levels in the group that received DHEA intervention, thus inferring the efficiency of DHEA in stress buffering.
Patients with the multiple endocrine neoplasia 1 (MEN1) syndrome develop various tumors during their lifetime. One of the rare manifestations observed in MEN1 patients is thymic neuroendocrine tumor (Th-NET) or thymic carcinoid, which is a major cause of death due to its aggressive nature, frequent recurrence, and lack of effective treatment. The goal of this study was to analyze the clinical presentation and outcome of Th-NETs in MEN1 patients at our institution and to investigate the correlation between genotype and phenotype. We evaluated the clinical characteristics of MEN1 patients with Th-NETs from a cohort of 350 patients with a MEN1 germline mutation and identified 13 patients (3.7%) with Th-NETs: 11 with thymic carcinoid, 1 with a thymoma demonstrating a neuroendocrine phenotype, and 1 with a non-neuroendocrine thymoma. Thymic carcinoid occurred exclusively in men and was the first tumor identified in 2 of the patients, while the 2 patients with thymoma were both females. Median age of diagnosis for Th-NETs was 43 years (range: 29-65 years). Mean tumor largest diameter was 7.18 cm (range: 2.5-15 cm). ACTH production was not detected in any of the thymic carcinoid cases. Seven patients died, 4 of them are still followed, and 2 of them were lost to follow-up. Th-NETs recurred following surgical resection in 7 patients. Family history of thymic carcinoid was identified in 6 patients. Smoking history was found in 6 patients. MEN1-associated tumors in our cohort included parathyroid adenoma (n=13), pancreatic NET (n=11), pituitary adenoma (n=8), Zollinger-Ellison syndrome (n=7), and lung carcinoid (n=1). In archived tumor samples obtained from 11 patients, chromogranin-A and synaptophysin immunohistochemistry confirmed the neuroendocrine phenotype in thymic carcinoids and showed neuroendocrine differentiation in one of the thymomas. Tumor grade analysis was performed using Ki-67 staining. Genomic DNA was isolated from peripheral blood leukocytes and the following MEN1 germline heterozygous mutations were identified: 8 frameshift, 3 nonsense, 1 in-frame deletion, and 1 missense mutation (found in a thymoma sample). The mutations were scattered throughout the entire MEN1 coding region without specific clustering. Moreover, the only genotype-phenotype correlation observed was a preponderance of protein truncating mutations (frameshift and nonsense) in the Th-NET cohort. Th-NETs are uncommon in MEN1 syndrome. Our Th-NET cohort showed a male predominance. MEN1 mutations in the Th-NET patients did not show any specific clustering, but a preponderance of protein truncating mutations was observed in the MEN1 gene. Further analysis of Th-NET samples for genetic alterations and gene expression profiles will help to uncover the yet to be determined modifying factors in the pathophysiology of Th-NETs.
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