Operational criteria application does not change clinicians' opinion on the diagnosis of mental disorder: a pre- and post-intervention validity study.

Objective: Our objective was to check if the ICD-10 operational criteria application changes non-operational, prototype-based diagnoses obtained in a real-life scenario. Methods: Psychiatry residents applied the diagnostic criteria of the ICD-10 as a "diagnostic test" to five outpatient patients they were already following who had a prototype-based diagnosis. Tests were used to ascertain whether changes in opinion were significant and if any of the diagnostic groups were more prone to change than others. The present paper is part of the study with UTN U1111-1260-1212. Results: Seventeen residents reviewed their last five case files, retrieving 85 diagnostic pairs of non-operational-based vs. operational-based diagnoses. The Stuart-Maxwell test did not indicate a significant opinion change (χ2 = 5.25, p = 0.39; power = 0.94) besides 30% of diagnostic changes. Despite not being statistically significant, 20.2% of all evaluations resulted in a change that would affect treatment choices. Using ICD-10 operational criteria slightly increased the number of observed diagnoses, but probably without clinical relevance. None of the non-operational diagnoses have a higher tendency to change with operational criteria application (χ2 = 11.6, p = 0.07). The female gender was associated with a higher diagnostic change tendency. Conclusion: Applying ICD-10 operational criteria as a diagnostic test does not induce a statistically significant diagnostic opinion change in residents and no diagnostic group seems more sensible to diagnostic change. Gender-related differences in diagnostic opinion changes might be evidence of sunk cost bias. Although not statistically significant, using operational criteria after diagnostic elaboration might help to deal with subjects without adequate treatment response.

Vitality, viability, long-term clonogenic survival, cytotoxicity, cytostasis and lethality: what do they mean when testing new investigational oncology drugs?

In the field of experimental therapeutics for oncology purposes researchers are continuously evaluating the toxicity of novel treatment approaches against cancer cells. Within this topic of research, it is highly critical to define parameters of toxicity that denote when cancer cells are perturbed in their functionality by a new investigational drug. As the goal for these approaches is to achieve cellular demise, then what approaches to use and what do they mean in terms of assessing such cell death is of critical importance. In this comment article we highlight the definition of vitality and differentiate it from viability, and further define clonogenic survival in a chronic fashion. Additionally, we highly recommend the use of the term cytotoxicity as a general descriptor indicating toxicity towards a cell, but within that we encourage to sub-classify it as either cytostasis (i.e., when a treatment does not allow a cell to grow but it does not kill it either), or lethality (when a cell dies in response to the treatment). A more precise use of these terms should help advance the field of experimental therapeutics in oncology towards better defining the mechanisms of action of novel investigational drugs.

Non-standard diagnostic assessment reliability in psychiatry: a study in a Brazilian outpatient setting using Kappa.

The use of Structured Diagnostic Assessments (SDAs) is a solution for unreliability in psychiatry and the gold standard for diagnosis. However, except for studies between the 50 s and 70 s, reliability without the use of Non-SDAs (NSDA) is seldom tested, especially in non-Western, Educated, Industrialized, Rich, and Democratic (WEIRD) countries. We aim to measure reliability between examiners with NSDAs for psychiatric disorders. We compared diagnostic agreement after clinician change, in an outpatient academic setting. We used inter-rater Kappa measuring 8 diagnostic groups: Depression (DD: F32, F33), Anxiety Related Disorders (ARD: F40-F49, F50-F59), Personality Disorders (PD: F60-F69), Bipolar Disorder (BD: F30, F31, F34.0, F38.1), Organic Mental Disorders (Org: F00-F09), Neurodevelopment Disorders (ND: F70-F99) and Schizophrenia Spectrum Disorders (SSD: F20-F29). Cohen's Kappa measured agreement between groups, and Baphkar's test assessed if any diagnostic group have a higher tendency to change after a new diagnostic assessment. We analyzed 739 reevaluation pairs, from 99 subjects who attended IPUB's outpatient clinic. Overall inter-rater Kappa was moderate, and none of the groups had a different tendency to change. NSDA evaluation was moderately reliable, but the lack of some prevalent hypothesis inside the pairs raised concerns about NSDA sensitivity to some diagnoses. Diagnostic momentum bias (that is, a tendency to keep the last diagnosis observed) may have inflated the observed agreement. This research was approved by IPUB's ethical committee, registered under the CAAE33603220.1.0000.5263, and the UTN-U1111-1260-1212.

Copper in Gynecological Diseases.

Copper (Cu) is an essential micronutrient for the correct development of eukaryotic organisms. This metal plays a key role in many cellular and physiological activities, including enzymatic activity, oxygen transport, and cell signaling. Although the redox activity of Cu is crucial for enzymatic reactions, this property also makes it potentially toxic when found at high levels. Due to this dual action of Cu, highly regulated mechanisms are necessary to prevent both the deficiency and the accumulation of this metal since its dyshomeostasis may favor the development of multiple diseases, such as Menkes' and Wilson's diseases, neurodegenerative diseases, diabetes mellitus, and cancer. As the relationship between Cu and cancer has been the most studied, we analyze how this metal can affect three fundamental processes for tumor progression: cell proliferation, angiogenesis, and metastasis. Gynecological diseases are characterized by high prevalence, morbidity, and mortality, depending on the case, and mainly include benign and malignant tumors. The cellular processes that promote their progression are affected by Cu, and the mechanisms that occur may be similar. We analyze the crosstalk between Cu deregulation and gynecological diseases, focusing on therapeutic strategies derived from this metal.

Auranofin Induces Lethality Driven by Reactive Oxygen Species in High-Grade Serous Ovarian Cancer Cells.

High-grade serous ovarian cancer (HGSOC) accounts for 70% of ovarian cancer cases, and the survival rate remains remarkably low due to the lack of effective long-term consolidation therapies. Clinical remission can be temporarily induced by platinum-based chemotherapy, but death subsequently results from the extensive growth of a platinum-resistant component of the tumor. This work explores a novel treatment against HGSOC using the gold complex auranofin (AF). AF primarily functions as a pro-oxidant by inhibiting thioredoxin reductase (TrxR), an antioxidant enzyme overexpressed in ovarian cancer. We investigated the effect of AF on TrxR activity and the various mechanisms of cytotoxicity using HGSOC cells that are clinically sensitive or resistant to platinum. In addition, we studied the interaction between AF and another pro-oxidant, L-buthionine sulfoximine (L-BSO), an anti-glutathione (GSH) compound. We demonstrated that AF potently inhibited TrxR activity and reduced the vitality and viability of HGSOC cells regardless of their sensitivities to platinum. We showed that AF induces the accumulation of reactive oxygen species (ROS), triggers the depolarization of the mitochondrial membrane, and kills HGSOC cells by inducing apoptosis. Notably, AF-induced cell death was abrogated by the ROS-scavenger N-acetyl cysteine (NAC). In addition, the lethality of AF was associated with the activation of caspases-3/7 and the generation of DNA damage, effects that were also prevented by the presence of NAC. Finally, when AF and L-BSO were combined, we observed synergistic lethality against HGSOC cells, which was mediated by a further increase in ROS and a decrease in the levels of the antioxidant GSH. In summary, our results support the concept that AF can be used alone or in combination with L-BSO to kill HGSOC cells regardless of their sensitivity to platinum, suggesting that the depletion of antioxidants is an efficient strategy to mitigate the course of this disease.

Cancer cell repopulation after therapy: which is the mechanism?

Cancer cell repopulation after therapy is a phenomenon that leads to therapeutic failure with the consequent relapse of the disease. The process is understudied and mechanisms need to be uncovered. Here we discuss the issue of cancer cell repopulation after chemo- and radio-therapies. We compile evidence alleging that the repopulation of cancer cells can be originated from either cancer stem cells resistant to therapy, cancer cells that in response to therapy become polyploid and thereafter germinate into near-diploid rapid proliferating cells, and/or cells that respond to treatment undergoing senescence as a transient mechanism to survive, followed by the reinitiation of the cell cycle. Approaches targeted to prevent this post-therapy cancer cell repopulation should be uncovered to prevent tumor relapse and thus increase overall survival from this devastating disease.

The metastatic capacity of high-grade serous ovarian cancer cells changes along disease progression: inhibition by mifepristone.

BACKGROUND: Simplistic two-dimensional (2D) in vitro assays have long been the standard for studying the metastatic abilities of cancer cells. However, tri-dimensional (3D) organotypic models provide a more complex environment, closer to that seen in patients, and thereby provide a more accurate representation of their true capabilities. Our laboratory has previously shown that the antiprogestin and antiglucocorticoid mifepristone can reduce the growth, adhesion, migration, and invasion of various aggressive cancer cells assessed using 2D assays. In this study, we characterize the metastatic capabilities of high-grade serous ovarian cancer cells generated along disease progression, in both 2D and 3D assays, and the ability of cytostatic doses of mifepristone to inhibit them. METHODS: High-grade serous ovarian cancer cells collected from two separate patients at different stages of their disease were used throughout the study. The 2D wound healing and Boyden chamber assays were used to study migration, while a layer of extracellular matrix was added to the Boyden chamber to study invasion. A 3D organotypic model, composed of fibroblasts embedded in collagen I and topped with a monolayer of mesothelial cells was used to further study cancer cell adhesion and mesothelial displacement. All assays were studied in cells, which were originally harvested from two patients at different stages of disease progression, in the absence or presence of cytostatic doses of mifepristone. RESULTS: 2D in vitro assays demonstrated that the migration and invasive rates of the cells isolated from both patients decreased along disease progression. Conversely, in both patients, cells representing late-stage disease demonstrated a higher adhesion capacity to the 3D organotypic model than those representing an early-stage disease. This adhesive behavior is associated with the in vivo tumor capacity of the cells. Regardless of these differences in adhesive, migratory, and invasive behavior among the experimental protocols used, cytostatic doses of mifepristone were able to inhibit the adhesion, migration, and invasion rates of all cells studied, regardless of their basal capabilities over simplistic or organotypic metastatic in vitro model systems. Finally, we demonstrate that when cells acquire the capacity to grow spontaneously as spheroids, they do attach to a 3D organotypic model system when pre-incubated with conditioned media. Of relevance, mifepristone was able to cause dissociation of these multicellular structures. CONCLUSION: Differences in cellular behaviours were observed between 2 and 3D assays when studying the metastatic capabilities of high-grade serous ovarian cancer cells representing disease progression. Mifepristone inhibited these metastatic capabilities in all assays studied.

Revisiting the Anti-Cancer Toxicity of Clinically Approved Platinating Derivatives.

Cisplatin (CDDP), carboplatin (CP), and oxaliplatin (OXP) are three platinating agents clinically approved worldwide for use against a variety of cancers. They are canonically known as DNA damage inducers; however, that is only one of their mechanisms of cytotoxicity. CDDP mediates its effects through DNA damage-induced transcription inhibition and apoptotic signalling. In addition, CDDP targets the endoplasmic reticulum (ER) to induce ER stress, the mitochondria via mitochondrial DNA damage leading to ROS production, and the plasma membrane and cytoskeletal components. CP acts in a similar fashion to CDDP by inducing DNA damage, mitochondrial damage, and ER stress. Additionally, CP is also able to upregulate micro-RNA activity, enhancing intrinsic apoptosis. OXP, on the other hand, at first induces damage to all the same targets as CDDP and CP, yet it is also capable of inducing immunogenic cell death via ER stress and can decrease ribosome biogenesis through its nucleolar effects. In this comprehensive review, we provide detailed mechanisms of action for the three platinating agents, going beyond their nuclear effects to include their cytoplasmic impact within cancer cells. In addition, we cover their current clinical use and limitations, including side effects and mechanisms of resistance.

The Transcoelomic Ecosystem and Epithelial Ovarian Cancer Dissemination.

Epithelial ovarian cancer (EOC) is considered the deadliest gynecological disease and is normally diagnosed at late stages, at which point metastasis has already occurred. Throughout disease progression, EOC will encounter various ecosystems and the communication between cancer cells and these microenvironments will promote the survival and dissemination of EOC. The primary tumor is thought to develop within the ovaries or the fallopian tubes, both of which provide a microenvironment with high risk of causing DNA damage and enhanced proliferation. EOC disseminates by direct extension from the primary tumors, as single cells or multicellular aggregates. Under the influence of cellular and non-cellular factors, EOC spheroids use the natural flow of peritoneal fluid to reach distant organs within the peritoneal cavity. These cells can then implant and seed distant organs or tissues, which develop rapidly into secondary tumor nodules. The peritoneal tissue and the omentum are two common sites of EOC metastasis, providing a microenvironment that supports EOC invasion and survival. Current treatment for EOC involves debulking surgery followed by platinum-taxane combination chemotherapy; however, most patients will relapse with a chemoresistant disease with tumors developed within the peritoneum. Therefore, understanding the role of the unique microenvironments that promote EOC transcoelomic dissemination is important in improving patient outcomes from this disease. In this review article, we address the process of ovarian cancer cellular fate at the site of its origin in the secretory cells of the fallopian tube or in the ovarian surface epithelial cells, their detachment process, how the cells survive in the peritoneal fluid avoiding cell death triggers, and how cancer- associated cells help them in the process. Finally, we report the mechanisms used by the ovarian cancer cells to adhere and migrate through the mesothelial monolayer lining the peritoneum. We also discuss the involvement of the transcoelomic ecosystem on the development of chemoresistance of EOC.

Interplay between nitric oxide and gonadotrophin-releasing hormone in the neuromodulation of the corpus luteum during late pregnancy in the rat.

BACKGROUND: Nitric oxide and GnRH are biological factors that participate in the regulation of reproductive functions. To our knowledge, there are no studies that link NO and GnRH in the sympathetic ganglia. Thus, the aim of the present work was to investigate the influence of NO on GnRH release from the coeliac ganglion and its effect on luteal regression at the end of pregnancy in the rat. METHODS: The ex vivo system composed by the coeliac ganglion, the superior ovarian nerve, and the ovary of rats on day 21 of pregnancy was incubated for 180 min with the addition, into the ganglionic compartment, of L-NG-nitro arginine methyl ester (L-NAME), a non-selective NO synthase inhibitor. The control group consisted in untreated organ systems. RESULTS: The addition of L-NAME in the coeliac ganglion compartment decreased NO as well as GnRH release from the coeliac ganglion. In the ovarian compartment, and with respect to the control group, we observed a reduced release of GnRH, NO, and noradrenaline, but an increased production of progesterone, estradiol, and expression of their limiting biosynthetic enzymes, 3ß-HSD and P450 aromatase, respectively. The inhibition of NO production by L-NAME in the coeliac ganglion compartment also reduced luteal apoptosis, lipid peroxidation, and nitrotyrosine, whereas it increased the total antioxidant capacity within the corpora lutea. CONCLUSION: Collectively, the results indicate that NO production by the coeliac ganglion modulates the physiology of the ovary and luteal regression during late pregnancy in rats.

Anticancer effects of mifepristone on human uveal melanoma cells.

BACKGROUND: Uveal melanoma (UM), the most prevalent intraocular tumor in adults, is a highly metastatic and drug resistant lesion. Recent studies have demonstrated cytotoxic and anti-metastatic effects of the antiprogestin and antiglucocorticoid mifepristone (MF) in vitro and in clinical trials involving meningioma, colon, breast, and ovarian cancers. Drug repurposing is a cost-effective approach to bring approved drugs with good safety profiles to the clinic. This current study assessed the cytotoxic effects of MF in human UM cell lines of different genetic backgrounds. METHODS: The effects of incremental concentrations of MF (0, 5, 10, 20, or 40 µM) on a panel of human UM primary (MEL270, 92.1, MP41, and MP46) and metastatic (OMM2.5) cells were evaluated. Cells were incubated with MF for up to 72 h before subsequent assays were conducted. Cellular functionality and viability were assessed by Cell Counting Kit-8, trypan blue exclusion assay, and quantitative label-free IncuCyte live-cell analysis. Cell death was analyzed by binding of Annexin V-FITC and/or PI, caspase-3/7 activity, and DNA fragmentation. Additionally, the release of cell-free DNA was assessed by droplet digital PCR, while the expression of progesterone and glucocorticoid receptors was determined by quantitative real-time reverse transcriptase PCR. RESULTS: MF treatment reduced cellular proliferation and viability of all UM cell lines studied in a concentration-dependent manner. A reduction in cell growth was observed at lower concentrations of MF, with evidence of cell death at higher concentrations. A significant increase in Annexin V-FITC and PI double positive cells, caspase-3/7 activity, DNA fragmentation, and cell-free DNA release suggests potent cytotoxicity of MF. None of the tested human UM cells expressed the classical progesterone receptor in the absence or presence of MF treatment, suggesting a mechanism independent of the modulation of the cognate nuclear progesterone receptor. In turn, all cells expressed non-classical progesterone receptors and the glucocorticoid receptor. CONCLUSION: This study demonstrates that MF impedes the proliferation of UM cells in a concentration-dependent manner. We report that MF treatment at lower concentrations results in cell growth arrest, while increasing the concentration leads to lethality. MF, which has a good safety profile, could be a reliable adjuvant of a repurposing therapy against UM.

The gold complex auranofin: new perspectives for cancer therapy.

Advanced stages of cancer are highly associated with short overall survival in patients due to the lack of long-term treatment options following the standard form of care. New options for cancer therapy are needed to improve the survival of cancer patients without disease recurrence. Auranofin is a clinically approved agent against rheumatoid arthritis that is currently enrolled in clinical trials for potential repurposing against cancer. Auranofin mainly targets the anti-oxidative system catalyzed by thioredoxin reductase (TrxR), which protects the cell from oxidative stress and death in the cytoplasm and the mitochondria. TrxR is over-expressed in many cancers as an adaptive mechanism for cancer cell proliferation, rendering it an attractive target for cancer therapy, and auranofin as a potential therapeutic agent for cancer. Inhibiting TrxR dysregulates the intracellular redox state causing increased intracellular reactive oxygen species levels, and stimulates cellular demise. An alternate mechanism of action of auranofin is to mimic proteasomal inhibition by blocking the ubiquitin-proteasome system (UPS), which is critically important in cancer cells to prevent cell death when compared to non-cancer cells, because of its role on cell cycle regulation, protein degradation, gene expression, and DNA repair. This article provides new perspectives on the potential mechanisms used by auranofin alone, in combination with diverse other compounds, or in combination with platinating agents and/or immune checkpoint inhibitors to combat cancer cells, while assessing the feasibility for its repurposing in the clinical setting.

Nelfinavir Induces Cytotoxicity towards High-Grade Serous Ovarian Cancer Cells, Involving Induction of the Unfolded Protein Response, Modulation of Protein Synthesis, DNA Damage, Lysosomal Impairment, and Potentiation of Toxicity Caused by Proteasome Inhibition.

High-grade serous ovarian cancer (HGSOC) is a significant cause of mortality among women worldwide. Traditional treatment consists of platinum-based therapy; however, rapid development of platinum resistance contributes to lower life expectancy, warranting newer therapies to supplement the current platinum-based protocol. Repurposing market-available drugs as cancer therapeutics is a cost- and time-effective way to avail new therapies to drug-resistant patients. The anti-HIV agent nelfinavir (NFV) has shown promising toxicity against various cancers; however, its role against HGSOC is unknown. Here, we studied the effect of NFV against HGSOC cells obtained from patients along disease progression and carrying different sensitivities to platinum. NFV triggered, independently of platinum sensitivity, a dose-dependent reduction in the HGSOC cell number and viability, and a parallel increase in hypo-diploid DNA content. Moreover, a dose-dependent reduction in clonogenic survival of cells escaping the acute toxicity was indicative of long-term residual damage. In addition, dose- and time-dependent phosphorylation of H2AX indicated NFV-mediated DNA damage, which was associated with decreased survival and proliferation signals driven by the AKT and ERK pathways. NFV also mediated a dose-dependent increase in endoplasmic reticulum stress-related molecules associated with long-term inhibition of protein synthesis and concurrent cell death; such events were accompanied by a proapoptotic environment, signaled by increased phospho-eIF2α, ATF4, and CHOP, increased Bax/Bcl-2 ratio, and cleaved executer caspase-7. Finally, we show that NFV potentiates the short-term cell cycle arrest and long-term toxicity caused by the proteasome inhibitor bortezomib. Overall, our in vitro study demonstrates that NFV can therapeutically target HGSOC cells of differential platinum sensitivities via several mechanisms, suggesting its prospective repurposing benefit considering its good safety profile.

Prenatal testosterone exposure induces insulin resistance, uterine oxidative stress and pro-inflammatory status in rats.

Prenatal androgen excess is considered one of the main causes of the development of polycystic ovary syndrome. In this study, we investigated the effect of prenatal hyperandrogenization (PH) on the physiology of the adult uterine tissue using a murine model of fetal programming caused by androgen excess in adult female rats. Pregnant rats were hyperandrogenized with testosterone and female offspring were studied when adult. Our results showed that PH leads to hyperglycemia and hyperinsulinemia. Consequently, PH developed insulin resistance and a systemic inflammatory state reflected by increased C-reactive protein. In the uterine tissue, levels of PPAR gamma-an important metabolic sensor in the endometrium-were found to be impaired. Moreover, PH induced a pro-inflammatory and an unbalanced oxidative state in the uterus reflected by increased COX-2, lipid peroxidation, and NF-κB. In summary, our results revealed that PH leads to a compromised metabolic state likely consequence of fetal reprogramming.

The Anti-Cancer Properties of the HIV Protease Inhibitor Nelfinavir.

Traditional cancer treatments may lose efficacy following the emergence of novel mutations or the development of chemoradiotherapy resistance. Late diagnosis, high-cost of treatment, and the requirement of highly efficient infrastructure to dispense cancer therapies hinder the availability of adequate treatment in low-income and resource-limited settings. Repositioning approved drugs as cancer therapeutics may reduce the cost and timeline for novel drug development and expedite the availability of newer, efficacious options for patients in need. Nelfinavir is a human immunodeficiency virus (HIV) protease inhibitor that has been approved and is extensively used as an anti-infective agent to treat acquired immunodeficiency syndrome (AIDS). Yet nelfinavir has also shown anti-cancer effects in in vitro and in vivo studies. The anti-cancer mechanism of nelfinavir includes modulation of different cellular conditions, such as unfolded protein response, cell cycle, apoptosis, autophagy, the proteasome pathway, oxidative stress, the tumor microenvironment, and multidrug efflux pumps. Multiple clinical trials indicated tolerable and reversible toxicities during nelfinavir treatment in cancer patients, either as a monotherapy or in combination with chemo- or radiotherapy. Since orally available nelfinavir has been a safe drug of choice for both adult and pediatric HIV-infected patients for over two decades, exploiting its anti-cancer off-target effects will enable fast-tracking this newer option into the existing repertoire of cancer chemotherapeutics.

The Capacity of High-Grade Serous Ovarian Cancer Cells to Form Multicellular Structures Spontaneously along Disease Progression Correlates with Their Orthotopic Tumorigenicity in Immunosuppressed Mice.

Many studies have examined the biology, genetics, and chemotherapeutic response of ovarian cancer's solid component; its liquid facet, however, remains critically underinvestigated. Floating within peritoneal effusions known as ascites, ovarian cancer cells form multicellular structures, creating a cancer niche in suspension. This study explores the pathobiology of spontaneously formed, multicellular, ovarian cancer structures derived from serous ovarian cancer cells isolated along disease evolution. It also tests their capacity to cause peritoneal disease in immunosuppressed mice. Results stem from an analysis of cell lines representing the most frequently diagnosed ovarian cancer histotype (high-grade serous ovarian cancer), derived from ascites of the same patient at distinct stages of disease progression. When cultured under adherent conditions, in addition to forming cellular monolayers, the cultures developed areas in which the cells grew upwards, forming densely packed multilayers that ultimately detached from the bottom of the plates and lived as free-floating, multicellular structures. The capacity to form foci and to develop multicellular structures was proportional to disease progression at the time of ascites extraction. Self-assembled in culture, these structures varied in size, were either compact or hollow, irregular, or spheroidal, and exhibited replicative capacity and an epithelial nature. Furthermore, they fully recreated ovarian cancer disease in immunosuppressed mice: accumulation of malignant ascites and pleural effusions; formation of discrete, solid, macroscopic, peritoneal tumors; and microscopic growths in abdominal organs. They also reproduced the histopathological features characteristic of high-grade serous ovarian cancer when diagnosed in patients. The following results encourage the development of therapeutic interventions to interrupt the formation and/or survival of multicellular structures that constitute a floating niche in the peritoneal fluid, which in turn halts disease progression and prevents recurrence.

Prenatally androgenized female rats develop uterine hyperplasia when adult.

Prenatal hyperandrogenization (PH) is hypothesized as one of the main factors contributing to the development of polycystic ovary syndrome (PCOS). In this study, we aimed to investigate the impact of prenatal exposure to androgen excess on the uterus when animals reach their adulthood. We found that PH altered the morphology of the uteri that show a hyperplastic morphology with increased total uterine thickness as well as luminal epithelium thickness, with both enhanced and altered distribution of glands as compared with controls. Morphological alterations were associated with an unbalanced homeostasis as assessed by the expression of regulators of cell cycle progression and cell death dynamics. PH also causes disturbances in the cell cycle of the uterine tissue and dysregulates cell death and survival pathways leading to the development of uterine hyperplasia. These findings suggest that PH may have a deleterious effect on the uterus.

Advanced assessment of migration and invasion of cancer cells in response to mifepristone therapy using double fluorescence cytochemical labeling.

BACKGROUND: Previous work in our laboratory demonstrated that antiprogestin mifepristone impairs the growth and adhesion of highly metastatic cancer cells, and causes changes in their cellular morphology. In this study, we further assess the anti-metastatic properties of mifepristone, by studying whether cytostatic doses of the drug can inhibit the migration and invasion of various cancer cell lines using a double fluorescence cytochemical labeling approach. METHODS: Cell lines representing cancers of the ovary (SKOV-3), breast (MDA-MB-231), glia (U87MG), or prostate (LNCaP) were treated with cytostatic concentrations of mifepristone. Wound healing and Boyden chamber assays were utilized to study cellular migration. To study cellular invasion, the Boyden chamber assay was prepared by adding a layer of extracellular matrix over the polycarbonate membrane. We enhanced the assays with the addition of double fluorescence cytochemical staining for fibrillar actin (F-actin) and DNA to observe the patterns of cytoskeletal distribution and nuclear positioning while cells migrate and invade. RESULTS: When exposed to cytostatic concentrations of mifepristone, all cancer cells lines demonstrated a decrease in both migration and invasion capacities measured using standard approaches. Double fluorescence cytochemical labeling validated that mifepristone-treated cancer cells exhibit reduced migration and invasion, and allowed to unveil a distinct migration pattern among the different cell lines, different arrays of nuclear localization during migration, and apparent redistribution of F-actin to the nucleus. CONCLUSION: This study reports that antiprogestin mifepristone inhibits migration and invasion of highly metastatic cancer cell lines, and that double fluorescence cytochemical labeling increases the value of well-known approaches to study cell movement.

High-Grade Serous Ovarian Cancer: Basic Sciences, Clinical and Therapeutic Standpoints.

Among a litany of malignancies affecting the female reproductive tract, that of the ovary is the most frequently fatal. Moreover, while the steady pace of scientific discovery has fuelled recent ameliorations in the outcomes of many other cancers, the rates of mortality for ovarian cancer have been stagnant since around 1980. Yet despite the grim outlook, progress is being made towards better understanding the fundamental biology of this disease and how its biology in turn influences clinical behaviour. It has long been evident that ovarian cancer is not a unitary disease but rather a multiplicity of distinct malignancies that share a common anatomical site upon presentation. Of these, the high-grade serous subtype predominates in the clinical setting and is responsible for a disproportionate share of the fatalities from all forms of ovarian cancer. This review aims to provide a detailed overview of the clinical-pathological features of ovarian cancer with a particular focus on the high-grade serous subtype. Along with a description of the relevant clinical aspects of this disease, including novel trends in treatment strategies, this text will inform the reader of recent updates to the scientific literature regarding the origin, aetiology and molecular-genetic basis of high-grade serous ovarian cancer (HGSOC).

Revitalising an academic pathology department: lessons learnt.

Pathology is a specialty that bridges basic medical science and clinical practice. In the era of personalised medicine, this specialty is facing unprecedented challenges. Some of these challenges are institution-specific, while many are shared worldwide at different magnitude. This review shares our team efforts in the past 5 years, 2012-2017, to revitalise a century-old academic pathology department in three aspects: administration, clinical service and academic development. The lessons learnt and insights gained from our experience may provide guidance to leaders in pathology or in other related specialties.