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Science Advances Jul 2023To understand the mechanism of acquired resistance to poly(ADP-ribose) polymerase inhibitors (PARPi) olaparib, we induced the formation of polyploid giant cancer cells...
To understand the mechanism of acquired resistance to poly(ADP-ribose) polymerase inhibitors (PARPi) olaparib, we induced the formation of polyploid giant cancer cells (PGCCs) in ovarian and breast cancer cell lines, high-grade serous cancer (HGSC)-derived organoids, and patient-derived xenografts (PDXs). Time-lapse tracking of ovarian cancer cells revealed that PGCCs primarily developed from endoreplication after exposure to sublethal concentrations of olaparib. PGCCs exhibited features of senescent cells but, after olaparib withdrawal, can escape senescence via restitutional multipolar endomitosis and other noncanonical modes of cell division to generate mitotically competent resistant daughter cells. The contraceptive drug mifepristone blocked PGCC formation and daughter cell formation. Mifepristone/olaparib combination therapy substantially reduced tumor growth in PDX models without previous olaparib exposure, while mifepristone alone decreased tumor growth in PDX models with acquired olaparib resistance. Thus, targeting PGCCs may represent a promising approach to potentiate the therapeutic response to PARPi and overcome PARPi-induced resistance.
Topics: Polyploidy; Ovarian Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Humans; Female; Mifepristone; Drug Resistance, Neoplasm; Cellular Senescence; Cell Line, Tumor; Apoptosis
PubMed: 37478190
DOI: 10.1126/sciadv.adf7195 -
BMJ Sexual & Reproductive Health Jul 2023
Topics: Humans; Mifepristone; Progesterone
PubMed: 36805893
DOI: 10.1136/bmjsrh-2022-201758 -
NEJM Evidence Jun 2024AbstractWith recent severe restrictions to abortion accessibility in the United States and a pending Supreme Court case challenging the Food and Drug Administration's... (Review)
Review
AbstractWith recent severe restrictions to abortion accessibility in the United States and a pending Supreme Court case challenging the Food and Drug Administration's approval of mifepristone, evidence-based strategies to protect and expand access to abortion care are needed. Two safe and effective regimens for medication abortion are widely used globally - misoprostol-only and misoprostol in combination with mifepristone. However, misoprostol-only regimens are rarely used in the United States. In 2023, the National Abortion Federation and the Society of Family Planning updated their recommended protocol for misoprostol-only for medication abortion to 800 μg of misoprostol administered buccally, sublingually, or vaginally every 3 hours for three or more doses. To characterize the data supporting this specific regimen, this article reviews the relevant literature to address the question of how effective misoprostol-only is for medication abortion. The authors conclude that the updated misoprostol regimen is highly effective and a potential strategy for expanding access to abortion.
Topics: Misoprostol; Humans; Female; Abortion, Induced; Pregnancy; Abortifacient Agents, Nonsteroidal; Mifepristone; United States
PubMed: 38804786
DOI: 10.1056/EVIDccon2300129 -
Current Opinion in Obstetrics &... Dec 2023To review the evidence-informed options for cervical preparation prior to second-trimester dilation and evacuation (D&E). (Review)
Review
PURPOSE OF REVIEW
To review the evidence-informed options for cervical preparation prior to second-trimester dilation and evacuation (D&E).
RECENT FINDINGS
As abortion restrictions increase and the number of abortion clinics and providers decreases, pregnant people are facing more barriers to abortion access. Those in need are now often required to travel for second-trimester abortion care, only to be faced with additional restrictions, such as mandatory waiting periods. Cervical preparation is recommended prior to D&E and takes time for effect. Given the increasing time required to obtain an abortion, patients and providers may prefer same-day cervical preparation to decrease the total time required. Options for same-day cervical preparation include misoprostol alone with single or serial doses, and misoprostol combined with osmotic dilators or transcervical balloon (Foley catheter). Same-day preparation may require additional clinical space to accommodate people after initiation of cervical preparation to manage side-effects and timing of the abortion. Overnight options are also used and more frequently later in the second trimester. Overnight options include mifepristone, osmotic dilators, and transcervical balloon and are often combined with same-day misoprostol. Medication alone preparation is well tolerated and effective in the second trimester, with the addition of mechanical methods with advancing gestation. With many options and combinations being safe and effective, providers can be dynamic and alter approach with supply shortages, adjust to different clinical settings, consider patient medical and surgical factors, and accommodate provider and patient preferences.
SUMMARY
Multiple pharmacologic and mechanical options have been shown to be safe and effective for cervical preparation prior to D&E. Consideration for multiple factors should influence the method of cervical preparation and methods may vary by patient, provider and setting.
Topics: Pregnancy; Female; Humans; Misoprostol; Pregnancy Trimester, Second; Abortifacient Agents, Nonsteroidal; Abortion, Induced; Mifepristone
PubMed: 37678155
DOI: 10.1097/GCO.0000000000000912 -
Journal of Medical Toxicology :... Jul 2023
Topics: Humans; United States; United States Food and Drug Administration; Drug Approval; Mifepristone
PubMed: 37233913
DOI: 10.1007/s13181-023-00949-z -
Brain : a Journal of Neurology Oct 2023Prolonged exposure to glucocorticoids, the main stress hormones, damages the brain and is a risk factor for depression and Alzheimer's disease. Two major drivers of...
Prolonged exposure to glucocorticoids, the main stress hormones, damages the brain and is a risk factor for depression and Alzheimer's disease. Two major drivers of glucocorticoid-related neurotoxicity are mitochondrial dysfunction and Tau pathology; however, the molecular/cellular mechanisms precipitating these events, and their causal relationship, remain unclear. Using cultured murine hippocampal neurons and 4-5-month-old mice treated with the synthetic glucocorticoid dexamethasone, we investigate the mechanisms underlying glucocorticoid-induced mitochondrial damage and Tau pathology. We find that glucocorticoids stimulate opening of the mitochondrial permeability transition pore via transcriptional upregulation of its activating component, cyclophilin D. Inhibition of cyclophilin D is protective against glucocorticoid-induced mitochondrial damage as well as Tau phosphorylation and oligomerization in cultured neurons. We further identify the mitochondrially-targeted compound mito-apocynin as an inhibitor of glucocorticoid-induced permeability transition pore opening, and show that this compound protects against mitochondrial dysfunction, Tau pathology, synaptic loss, and behavioural deficits induced by glucocorticoids in vivo. Finally, we demonstrate that mito-apocynin and the glucocorticoid receptor antagonist mifepristone rescue Tau pathology in cytoplasmic hybrid cells, an ex vivo Alzheimer's disease model wherein endogenous mitochondria are replaced with mitochondria from Alzheimer's subjects. These findings show that mitochondrial permeability transition pore opening is a precipitating factor in glucocorticoid-induced mitochondrial dysfunction, and that this event stimulates Tau pathogenesis. Our data also link glucocorticoids to mitochondrial dysfunction and Tau pathology in the context of Alzheimer's disease and suggest that mitochondria are promising therapeutic targets for mitigating stress- and Tau-related brain damage.
Topics: Humans; Mice; Animals; Infant; Alzheimer Disease; Glucocorticoids; Peptidyl-Prolyl Isomerase F; Mitochondrial Permeability Transition Pore
PubMed: 37070763
DOI: 10.1093/brain/awad127 -
Contraception Oct 2023This study aimed to review clinical practice outcomes of early pregnancy loss (EPL) medical management using mifepristone and misoprostol outside of a clinical trial... (Review)
Review
OBJECTIVES
This study aimed to review clinical practice outcomes of early pregnancy loss (EPL) medical management using mifepristone and misoprostol outside of a clinical trial setting.
STUDY DESIGN
In this retrospective cohort study, we reviewed a deidentified database of patients who received mifepristone-misoprostol for EPL from May 2018 to May 2021 at our academic center-based clinic, which was a study site for a multicenter mifepristone-misoprostol EPL trial completed in March 2018. All patients received mifepristone 200 mg orally and misoprostol 800 mcg vaginally or buccally, with clinic follow-up typically scheduled within 1 week. The primary outcome was successful medical management, defined as management without the need for aspiration, and the secondary outcomes included additional interventions and indications, follow-up ultrasonography findings, and adverse events requiring treatment.
RESULTS
We treated 90 patients with a median ultrasound-measured gestational size of 49 (range 30-80) days and median time from mifepristone to misoprostol of 24 (range 8-66) hours. Follow-up was completed in clinic by 80 (88.9%), completed remotely by five (5.6%), and not completed by five (5.6%) patients. Overall, 76 (95% CI 82.9%-96.0%) of 85 patients (89.4%) with follow-up were successfully managed without uterine aspiration. Eighty patients had initial follow-up ultrasonography interpreted as gestational sac expulsion; seven (8.8%) of these ultimately underwent aspiration, including one patient who had a previously undiagnosed cesarean scar ectopic pregnancy. Two patients had significant safety outcomes: one pelvic infection and one blood transfusion during aspiration in the patient with a cesarean scar ectopic pregnancy.
CONCLUSIONS
Outside of a clinical trial setting, medical management of EPL with mifepristone and misoprostol remains effective and safe.
IMPLICATIONS
Medical management of EPL with mifepristone and misoprostol is effective and safe outside of a clinical trial setting. A standardized protocol based on the best available clinical trial evidence can be used in clinical practice for the medical management of EPL.
Topics: Pregnancy; Female; Humans; Mifepristone; Misoprostol; Abortion, Spontaneous; Abortifacient Agents, Nonsteroidal; Abortifacient Agents, Steroidal; Retrospective Studies; Cicatrix; Abortion, Induced; Pregnancy, Ectopic; Multicenter Studies as Topic
PubMed: 37524147
DOI: 10.1016/j.contraception.2023.110134 -
Cureus Nov 2023Mifepristone and misoprostol are globally used medications that have become disparaged through the stigmatization of reproductive healthcare. Patients are hindered from... (Review)
Review
Mifepristone and misoprostol are globally used medications that have become disparaged through the stigmatization of reproductive healthcare. Patients are hindered from receiving prompt treatment in clinical scenarios where misoprostol and mifepristone are the drugs of choice. It is no exaggeration to emphasize that in cases where reproductive healthcare is concerned. The aim of this paper is to discuss the different indications of mifepristone and to delineate where the discrepancy in accessibility arises. For this systematic review, we included publications citing clinical trials involving the use and efficacy of mifepristone published in English within the date range of 2000 to 2023. Five databases were searched to identify relevant sources. These databases are Google Scholar, MEDLINE with full text through EBSCO, and three National Center for Biotechnology Information (NCBI) databases (NCBI Bookshelf, PubMed, and PubMed Central). Twenty-three records were ultimately included in this review. Mifepristone has been shown to have therapeutic effects in the treatment of psychiatric disorders, such as major depressive disorder and psychotic depression. There was a significant decrease in depression and psychiatric rating symptoms for patients taking mifepristone versus placebo with no adverse events. Mifepristone has also been shown to improve treatment course in patients with Cushing's disease (CD) who failed or are unable to undergo surgical treatment. In addition, mifepristone has been shown to be a successful treatment option for adenomyosis and leiomyomas. Patients had a statistically significant decrease in uterine volumes following mifepristone treatment, which aided in the alleviation of other symptoms, such as blood loss and pelvic discomfort. Mifepristone is a synthetic steroid that has immense potential to provide symptomatic relief in patients suffering from a wide array of complicated diseases. Historically, mifepristone has been proven to have an incredible safety profile. While further research is certainly needed, the politicization of its medical use for only one of its many indications has unfortunately led to the willful ignorance of its potential despite its evidence-based safety profile and efficacy.
PubMed: 38060710
DOI: 10.7759/cureus.48372 -
Stress (Amsterdam, Netherlands) Nov 2023As the end product of the hypothalamus-pituitary-adrenal (HPA) axis, the glucocorticoid hormones cortisol and corticosterone coordinate circadian activities,... (Review)
Review
As the end product of the hypothalamus-pituitary-adrenal (HPA) axis, the glucocorticoid hormones cortisol and corticosterone coordinate circadian activities, stress-coping, and adaptation to change. For this purpose, the hormone promotes energy metabolism and controls defense reactions in the body and brain. This life-sustaining action exerted by glucocorticoids occurs in concert with the autonomic nervous and immune systems, transmitters, growth factors/cytokines, and neuropeptides. The current contribution will focus on the glucocorticoid feedback paradox in the HPA-axis: the phenomenon that stress responsivity remains resilient if preceded by stress-induced secretion of glucocorticoid hormone, but not if this hormone is previously administered. Furthermore, in animal studies, the mixed progesterone/glucocorticoid antagonist RU486 or mifepristone switches to an apparent partial agonist upon repeated administration. To address these enigmas several interesting phenomena are highlighted. These include the conditional nature of the excitation/inhibition balance in feedback regulation, the role of glucose as a determinant of stress responsivity, and the potential of glucocorticoids in resetting the stress response system. The analysis of the feedback paradox provides also a golden opportunity to review the progress in understanding the role of glucocorticoid hormone in resilience and vulnerability during stress, the science that was burned deeply in Mary Dallman's emotions.
Topics: Animals; Glucocorticoids; Feedback; Stress, Psychological; Corticosterone; Hydrocortisone
PubMed: 37589046
DOI: 10.1080/10253890.2023.2247090