-
International Journal of Cell Biology 2023Inducible gene regulation methods are indispensable in diverse biological applications, yet many of them have severe limitations in their applicability. These include...
Inducible gene regulation methods are indispensable in diverse biological applications, yet many of them have severe limitations in their applicability. These include inducer toxicity, a limited variety of organisms the given system can be used in, and side effects of the induction method. In this study, a novel inducible system, the , was created using a mutant ligand-binding domain of the glucocorticoid receptor (CS1/CD), used together with various genetic elements such as the Gal4 DNA-binding domain or Cre recombinase. The RuX system is shown to be capable of over 1000-fold inducibility, has flexible applications, and is offered for use in cell cultures.
PubMed: 37941807
DOI: 10.1155/2023/7121512 -
Cancer Research Communications Dec 2023Disease progression following androgen ablation was shown to be associated with upregulation of the glucocorticoid receptor (GR). Longitudinal monitoring of GR...
UNLABELLED
Disease progression following androgen ablation was shown to be associated with upregulation of the glucocorticoid receptor (GR). Longitudinal monitoring of GR expression in circulating extracellular vesicles (EV) may reflect changes in the tumor cell and facilitates detection of acquired resistance. We utilized LNCaP, LREX cells and a patient-derived xenograft, MDA PDX 322-2-6a, for in vitro and in vivo experiments. Plasma-derived EVs were isolated from patients with localized high-risk prostate cancer undergoing androgen ablation. The mRNA levels of GR in EVs and their responsive genes were detected by transcriptome analysis, qRT-PCR and the protein levels by Western blot analysis. We detected changes in GR expression at mRNA and protein levels in EVs derived from LNCaP and LREX cells in in vitro studies. In in vivo experiments, LNCaP and the PDX MDA 322-2-6a-bearing mice were treated with enzalutamide. GR levels in plasma-derived EVs were increased only in those tumors that did not respond to enzalutamide. Treatment of mice bearing enzalutamide-resistant tumors with a GR inhibitor in combination with enzalutamide led to a transient pause in tumor growth in a subset of tumors and decreased GR levels intracellular and in plasma-derived EVs. In a subgroup of patients with high-risk localized prostate cancer treated with androgen signaling inhibition, GR was found upregulated in matching tissue and plasma EVs. These analyses showed that GR levels in plasma-derived EVs may be used for monitoring the transition of GR expression allowing for early detection of resistance to androgen ablation treatment.
SIGNIFICANCE
Longitudinal monitoring of GR expression in plasma-derived EVs from patients with prostate cancer treated with androgen signaling inhibitors facilitates early detection of acquisition of resistance to androgen receptor signaling inhibition in individual patients.
Topics: Receptors, Glucocorticoid; Extracellular Vesicles; Biomarkers; Signal Transduction; Humans; Animals; Mice; Male; Cell Line, Tumor; Phenylthiohydantoin; Antineoplastic Agents; Drug Resistance, Neoplasm; Gene Expression Regulation; Prostatic Neoplasms; Mifepristone
PubMed: 37930121
DOI: 10.1158/2767-9764.CRC-23-0362 -
Cureus Oct 2023Medical termination of pregnancy, also known as medication abortion, is a safe and effective method of terminating pregnancies in the early stages. It involves using... (Review)
Review
Medical termination of pregnancy, also known as medication abortion, is a safe and effective method of terminating pregnancies in the early stages. It involves using medications, such as mifepristone and prostaglandin, to induce a miscarriage. The success rates of medical abortion vary depending on factors such as gestational age and the specific medications used. For pregnancies that are 49 days or less, the success rates range from 92% to 98%. The choice between misoprostol and gemeprost, both prostaglandins, does not significantly impact the outcomes. It is important to note that various factors, including study design, definitions of success, and prior experience with medical abortion may influence success rates. Strict criteria for success and limited familiarity with the procedure may result in lower reported success rates. Medical termination of pregnancy should be carried out under the guidance and supervision of healthcare professionals. It is crucial to consult a healthcare provider to receive accurate information, personalized guidance, and appropriate support throughout the process. Each situation is unique, and decisions regarding medical termination of pregnancy should be made in collaboration with a trusted healthcare provider.
PubMed: 37927767
DOI: 10.7759/cureus.46444 -
Reproductive Biology and Endocrinology... Oct 2023
PubMed: 37907948
DOI: 10.1186/s12958-023-01158-7 -
Pharmaceuticals (Basel, Switzerland) Sep 2023Although cisplatin is an effective chemotherapy drug used against many types of cancer, it has poor bioavailability, produces severe adverse effects, and frequently...
Although cisplatin is an effective chemotherapy drug used against many types of cancer, it has poor bioavailability, produces severe adverse effects, and frequently leads to tumor resistance. Consequently, more effective formulations are needed. The co-administration of cisplatin with mifepristone, which counters an efflux pump drug-resistance mechanism in tumor cells, has shown important synergism, but without resolving the problem of poor bioavailability. Specificity to tumor tissue and bioavailability have been improved by co-encapsulating cisplatin and mifepristone in a liposomal formulation (L-Cis/MF), which needs further research to complete pre-clinical requirements. The aim of this current contribution was to conduct a pharmacokinetic study of cisplatin and mifepristone in male Wistar rats after administration of L-Cis/MF and the conventional (unencapsulated) formulation. Additionally, the capacity of L-Cis/MF to reduce tumor growth in male nude mice was evaluated following the implantation of xenografts of non-small-cell lung cancer. The better pharmacokinetics (higher plasma concentration) of cisplatin and mifepristone when injected in the liposomal versus the conventional formulation correlated with greater efficacy in controlling tumor growth. Future research on L-Cis/MF will characterize its molecular mechanisms and apply it to other types of cancer affected by the synergism of cisplatin and mifepristone.
PubMed: 37895808
DOI: 10.3390/ph16101337 -
JAMA Network Open Oct 2023Misoprostol-alone regimens for abortion may be more effective than previously thought. (Observational Study)
Observational Study
IMPORTANCE
Misoprostol-alone regimens for abortion may be more effective than previously thought.
OBJECTIVE
To estimate the effectiveness of medication abortion with misoprostol alone among individuals self-managing their abortion.
DESIGN, SETTING, AND PARTICIPANTS
For this prospective observational cohort study of callers to safe abortion hotlines and accompaniment groups in Argentina, Nigeria, and Southeast Asia, participants were recruited between July 31, 2019, and October 1, 2020, prior to starting their medication abortion. Eligible participants were 13 years or older, had no contraindications to medication abortion, and were not currently bleeding. Participants completed a baseline and 2 follow-up surveys. The analysis was restricted to participants who reported using misoprostol alone and was performed between January 6, 2022 and September 8, 2023.
EXPOSURE
Self-managed medication abortion using misoprostol alone.
MAIN OUTCOMES AND MEASURES
The primary outcome was effectiveness, defined as participant self-report of complete abortion without procedural intervention, measured at 1 week and 3 weeks after taking misoprostol. Secondary outcomes included method safety, measured by self-report of experiencing warning signs (eg, heavy bleeding, pain, fever, discharge) indicative of a potential complication and by medical treatment (eg, blood transfusion, intravenous fluids, overnight hospital stay) indicative of a potential adverse event. Additional outcomes included length of bleeding and cramping, time to expulsion, and experience of adverse effects.
RESULTS
Among 1352 enrolled participants, 637 used misoprostol-alone regimens for abortion and were included in the analysis (591 [92.8%] from Nigeria, 45 [7.1%] from Southeast Asia, and 1 [0.2%] from Argentina; 384 [60.2%] aged 20-29 years; 317 [49.8%] with pregnancy durations <7 weeks and 205 [32.2%] with pregnancy durations between 7 and <9 weeks). At last follow-up after taking medication (median, 22 days; IQR, 21-26 days), 625 participants (98.1%; 95% CI, 96.7%-98.9%) had a complete abortion without procedural intervention. Potential adverse events were reported by 6 participants (0.9%; 95% CI, 0.4%-2.1%). Most participants experienced bleeding for less than 1 week (median, 4 days; IQR, 3-6 days) and expelled their pregnancy within 24 hours of starting the abortion process (median, 12 hours; IQR, 9-15 hours). Common side effects included nausea (335 participants [52.6%]), fever (232 [36.4%]), and diarrhea (181 [28.4%]).
CONCLUSIONS AND RELEVANCE
The findings suggest that misoprostol alone is a highly effective method of pregnancy termination. Future research should explore strategies to maximize the effectiveness of misoprostol alone in clinical and nonclinical settings.
Topics: Pregnancy; Female; Humans; Misoprostol; Prospective Studies; Mifepristone; Abortion, Induced; Abortion, Spontaneous
PubMed: 37889485
DOI: 10.1001/jamanetworkopen.2023.40042 -
BMJ Sexual & Reproductive Health Jan 2024We sought to determine whether there is evidence to recommend progesterone for individuals not wishing to complete a medication abortion after taking mifepristone.
BACKGROUND
We sought to determine whether there is evidence to recommend progesterone for individuals not wishing to complete a medication abortion after taking mifepristone.
METHODS
We undertook an updated systematic review including a primary search for studies in which individuals received progesterone to reverse the effects of mifepristone, and a secondary search for studies in which individuals received mifepristone alone. We searched PubMed, Embase, Cochrane, CINAHL and grey literature up to December 2022. We used the Joanna Briggs Institute critical appraisal tools for risk of bias assessment. We compared ongoing pregnancy rates among individuals treated with progesterone to those managed expectantly.
RESULTS
We did not find new studies in our secondary search. For the main search, we included three case series and one randomised controlled trial. Data were available for 561 individuals who received progesterone after mifepristone, of whom 271 (48%) had ongoing pregnancies. The quality of the evidence in the case series was low due to methodological and ethical issues. Enrollment in the randomised trial stopped early due to bleeding events in both arms. The ongoing pregnancy rate for individuals ≤7 weeks who received progesterone was 42% (95% CI 37-48) compared with 22% (95% CI 11-39) for mifepristone alone. At 7-8 weeks, the ongoing pregnancy rate was 62% (95% CI 52-71) in the progesterone group and 50% (95% CI 15- 85) in the mifepristone alone group.
CONCLUSION
Based mostly on poor-quality data, it appears the ongoing pregnancy rate in individuals treated with progesterone after mifepristone is not significantly higher compared to that of individuals receiving mifepristone alone.
Topics: Pregnancy; Female; Humans; Progesterone; Mifepristone; Abortion, Induced; Pregnancy Rate
PubMed: 37863512
DOI: 10.1136/bmjsrh-2023-201875 -
Journal of Cancer 2023Silencing of heat shock protein 60 (HSP60) suppresses the growth of hepatocellular carcinoma (HCC). Mifepristone inhibits mRNA expression in -infected epithelial cells....
Silencing of heat shock protein 60 (HSP60) suppresses the growth of hepatocellular carcinoma (HCC). Mifepristone inhibits mRNA expression in -infected epithelial cells. The aim of this study was to determine whether mifepristone could inhibit the growth of HCC cells by affecting the functions of HSP60. The effect of mifepristone on cell viability was examined by flow cytometry and a cell proliferation assay. Protein-protein interactions were examined using the immunoprecipitation assay. The anti-tumor effect of mifepristone was evaluated using a xenograft model. Our results indicated that mifepristone induces cell cycle arrest at the G1 phase and early-stage apoptosis in HCC cells. Instead of reducing the total amount of HSP60, mifepristone induced the release of mitochondrial HSP60 into the cytosol by causing a loss of ΔΨm, thereby enhancing glucocorticoid receptor (GR)-HSP60-survivin complex formation as well as survivin degradation. Animal models have confirmed the growth inhibitory effects of mifepristone on HCC, including changes in the abundance of HSP60 in mitochondria and cytosol, decreased survivin and Ki-67-positive cells, as well as increased cell apoptosis. In conclusion, the inhibition of HCC growth by mifepristone may be achieved by altering the subcellular distribution of HSP60 to enhance the formation of cytosolic GR-HSP60-survivin complexes in the cells, leading to the degradation of survivin.
PubMed: 37859823
DOI: 10.7150/jca.86611 -
Gynecological Endocrinology : the... Dec 2023This study is aimed to determine the efficacy of a cocktail style treatment by combining GnRH-antagonist, letrozole, and mifepristone on the prevention of ovarian... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
This study is aimed to determine the efficacy of a cocktail style treatment by combining GnRH-antagonist, letrozole, and mifepristone on the prevention of ovarian hyperstimulation syndrome (OHSS) in high-risk women.
METHODS
This prospective, randomized controlled clinical trial was performed between January 2018 and December 2018. A total of 170 women who identified as high risk of OHSS during the ovarian hyperstimulation and underwent cryopreservation of whole embryos. On the day of oocyte retrieval, the combination group received 0.25 mg Cetrorelix for 3 d, 5 mg letrozole for 5 d, and 50 mg mifepristone for 3 d, the mifepristone group received 50 mg mifepristone for 3 d. A total of 156 cases were included in final analysis. All the frozen embryo transfer (FET) cycles were followed up until December 2021.
RESULTS
The combination group showed significantly decreased incidence of moderate and severe OHSS than mifepristone group (20.5% 42.3%), with remarkably reduced serum estradiol level on hCG + 3 and + 5 d, decreased ovarian diameter, and shortened luteal phase. Oocyte retrieval number, levels of estradiol on hCG + 0 and VEGF, and ovarian diameter on hCG + 5 were associated with the severity of the symptoms. There was no significant difference in cumulative live birth rates (LBRs) between the combination and mifepristone group (74.4% . 76.9%).
CONCLUSIONS
The combination treatment effectively reduces the incidence of moderate/severe OHSS in high-risk women.
Topics: Female; Humans; Ovarian Hyperstimulation Syndrome; Letrozole; Mifepristone; Fertilization in Vitro; Prospective Studies; Estradiol; Gonadotropin-Releasing Hormone; Hormone Antagonists; Ovulation Induction
PubMed: 37844908
DOI: 10.1080/09513590.2023.2269281 -
Cancers Sep 2023Triple-negative breast cancer (TNBC) is considered one of the most aggressive forms of breast cancer with poor survival rates compared to other breast cancer subtypes.... (Review)
Review
Triple-negative breast cancer (TNBC) is considered one of the most aggressive forms of breast cancer with poor survival rates compared to other breast cancer subtypes. TNBC is characterized by the absence of the estrogen receptor alpha, progesterone receptor, and the human epidermal growth factor receptor 2, limiting those viable treatment options available to patients with other breast cancer subtypes. Furthermore, due to the particularly high heterogeneity of TNBC, conventional treatments such as chemotherapy are not universally effective, leading to drug resistance and intolerable side effects. Thus, there is a pressing need to discover new therapies beneficial to TNBC patients. This review highlights current findings regarding the roles of three steroid hormone receptors, estrogen receptor beta, the androgen receptor, and the glucocorticoid receptor, in the progression of TNBC. In addition, we discussed several ongoing and completed clinical trials targeting these hormone receptors in TNBC patients.
PubMed: 37835396
DOI: 10.3390/cancers15194702