Endometriosis in the Mouse: Challenges and Progress Toward a ‘Best Fit’ Murine Model

Endometriosis is a prevalent gynecologic condition associated with pelvic pain and infertility characterized by the implantation and growth of endometrial tissue displaced into the pelvis via retrograde menstruation. The mouse is a molecularly well-annotated and cost-efficient species for modeling human disease in the therapeutic discovery pipeline. However, as a non-menstrual species with a closed tubo-ovarian junction, the mouse poses inherent challenges as a preclinical model for endometriosis research. Over the past three decades, numerous murine models of endometriosis have been described with varying degrees of fidelity in recapitulating the essential pathophysiologic features of the human disease. We conducted a search of the peer-reviewed literature to identify publications describing preclinical research using a murine model of endometriosis. Each model was reviewed according to a panel of ideal model parameters founded on the current understanding of endometriosis pathophysiology. Evaluated parameters included method of transplantation, cycle phase and type of tissue transplanted, recipient immune/ovarian status, iterative schedule of transplantation, and option for longitudinal lesion assessment. Though challenges remain, more recent models have incorporated innovative technical approaches such as in vivo fluorescence imaging and novel hormonal preparations to overcome the unique challenges posed by murine anatomy and physiology. These models offer significant advantages in lesion development and readout toward a high-fidelity mouse model for translational research in endometriosis.

Comparative advantage of anti-Mullerian hormone over other ovarian reserve metric (basal hormonal test) in prediction of fertility in women with varying menstrual cycle

Objective: Anti-Mullerian hormone has been indicated as a novel biomarker for ovarian reserve assessment. This study aimed to determine the comparative advantage of serum levels of AMH, FSH, LH, E2, and LH/FSH ratio among women with varying menstrual cycles and duration of menstruation. Material and Method: A total of 90 subjects, which consisted of sixty subjects and thirty healthy subjects as control, were recruited. Blood samples were collected on day 3 of the menstrual cycle and evaluated for ovarian markers using the ELISA technique. All data were analyzed using SPSS version 23.0. Results: AMH and LH/FSH levels were lower in women with varying menstrual cycles than in the control group. FSH, LH, and E2 levels were significantly higher in women with varying menstrual cycles and flow duration than in the control group(P<0.05). AMH was negatively correlated with age (r= -0.72), BMI( r= -0.4), FSH(r= - 0.3), LH(r = -0.2) (p<0.05) and E2(r= -0.2, p>0.05). Also age was positively correlated with FSH(r=0.5,p<0.05), E2(r=0.3, p<0.05) and BMI(r=0.4, p<0.05). The level of AMH was not significant with cycle length and days of flow(p>0.05). This implies that AMH can be measured independently of the cycle phase. This show that AMH was lower in women with varying menstrual cycle with an increase in gonadotrophin and E2. The strong negative relationship between age and AMH implies that age is determining factor of ovarian reserve. Conclusion: AMH combined with age and FSH may improve ovarian reserve evaluation, making AMH a better marker

Transcriptomics of receptive endometrium in women with sonographic features of adenomyosis

Background Women with uterine adenomyosis seeking assisted reproduction have been associated with compromised endometrial receptivity to embryo implantation. To understand the mechanisms involved in this process, we aimed to compare endometrial transcriptome profiles during the window of implantation (WOI) between women with and without adenomyosis. Methods We obtained endometrial biopsies LH-timed to the WOI from women with sonographic features of adenomyosis (n=10) and controls (n=10). Isolated RNA samples were subjected to RNA sequencing (RNA-seq) by the Illumina NovaSeq 6000 platform and endometrial receptivity classification with a molecular tool for menstrual cycle phase dating (beREADY®, CCHT). The program language R and Bioconductor packages were applied to analyse RNA-seq data in the setting of the result of accurate endometrial dating. To suggest robust candidate pathways, the identified differentially expressed genes (DEGs) associated with the adenomyosis group in the receptive phase were further integrated with 151, 173 and 42 extracted genes from published studies that were related to endometrial receptivity in healthy uterus, endometriosis and adenomyosis, respectively. Enrichment analyses were performed using Cytoscape ClueGO and CluePedia apps. Results Out of 20 endometrial samples, 2 were dated to the early receptive phase, 13 to the receptive phase and 5 to the late receptive phase. Comparison of the transcriptomics data from all 20 samples provided 909 DEGs (p<0.05; nonsignificant after adjusted p value) in the adenomyosis group but only 4 enriched pathways (Bonferroni p value < 0.05). The analysis of 13 samples only dated to the receptive phase provided suggestive 382 DEGs (p<0.05; nonsignificant after adjusted p value) in the adenomyosis group, leading to 33 enriched pathways (Bonferroni p value < 0.05). These included pathways were already associated with endometrial biology, such as “Expression of interferon (IFN)-induced genes” and “Response to IFN-alpha”. Data integration revealed pathways indicating a unique effect of adenomyosis on endometrial molecular organization (e.g., “Expression of IFN-induced genes”) and its interference with endometrial receptivity establishment (e.g., “Extracellular matrix organization” and “Tumour necrosis factor production”). Conclusions Accurate endometrial dating and RNA-seq analysis resulted in the identification of altered response to IFN signalling as the most promising candidate of impaired uterine receptivity in adenomyosis.

Combination of Abemaciclib following Eribulin Overcomes Palbociclib-Resistant Breast Cancer by Inhibiting the G2/M Cell Cycle Phase

Breast cancer remains a leading cancer burden among women worldwide. Acquired resistance of cyclin-dependent kinase (CDK) 4/6 inhibitors occurs in almost all hormone receptor (HR)-positive subtype cases, comprising 70% of breast cancers, although CDK4/6 inhibitors combined with endocrine therapy are highly effective. CDK4/6 inhibitors are not expected to cooperate with cytotoxic chemotherapy based on the basic cytotoxic chemotherapy mode of action that inhibits rapidly proliferating cells. The palbociclib-resistant preclinical model developed in the current study investigated whether the combination of abemaciclib, CDK4/6 inhibitor with eribulin, an antimitotic chemotherapy could be a strategy to overcome palbociclib-resistant HR-positive breast cancer. The current study demonstrated that sequential abemaciclib treatment following eribulin synergistically suppressed CDK4/6 inhibitor-resistant cells by inhibiting the G2/M cell cycle phase more effectively. The current study showed the significant association of the pole-like kinase 1 (PLK1) level and palbociclib resistance. Moreover, the cumulative PLK1 inhibition in the G2/M phase by each eribulin or abemaciclib proved to be a mechanism of the synergistic effect. The synergistic antitumor effect was also supported by in vivo study. The sequential combination of abemaciclib following eribulin merits further clinical trials to overcome resistance to CDK4/6 inhibitors in HR-positive breast cancer.

PHASES OF THE LIFE CYCLE OF UNIVERSITY SCIENTIFIC AND PEDAGOGICAL SPECIALIST’S BRAND

The article considers the life cycle of a university scientific and pedagogical specialist's brand as a continuous period from the moment of gaining a high level of recognition by the target audience to the moment of loss of specified influence on the target audience. A direct correlation between the phases of a university scientific and pedagogical specialist's brand life cycle and starting points of the theory of innovation diffusion is proved there. The division of the life cycle of a brand into six phases is proposed. They are as follows: phase of development of branding technology, phase of the introduction of a university scientific and pedagogical specialistʼs brand into the educational and scientific activity of a university, phase of growth of personal and professional potential of a brand, phase of stabilization of interaction of image and reputation brand components; the phase of extinction of the university specialist’s brand and the phase of the brandʼs exit from the market of providing educational and scientific services. The inexpediency of purposefully avoiding the development phase of branding technology is argued, as such “dynamically oriented” branding does not take into account the peculiarities of the personal and professional potential of the specialist, as well as lacks systemic and strategic focus. It is specified that depending on the purpose of application, rebranding of the university professor’s brand can act as a connecting phase of a life cycle of a specialists’ brand and as a singular process of formation of a new university professor’s brand. It is emphasized that preventive or forced-consolidating rebranding by a university professor due to fixing a temporary decline in his brand demand by the target audience in a phase of growth of personal and professional potential is ineffective. Keywords: brand; university professor; life cycle; phase; differentiation; target audience; university; rebranding.

New Heterocyclic Combretastatin A-4 Analogs: Synthesis and Biological Activity of Styryl-2(3H)-Benzothiazolones

Here, we describe the synthesis, characterization, and biological activities of a series of 26 new styryl-2(3H)-benzothiazolone analogs of combretastatin-A4 (CA-4). The cytotoxic activities of these compounds were tested in several cell lines (EA.hy926, A549, BEAS-2B, MDA-MB-231, HT-29, MCF-7, and MCF-10A), and the relations between structure and cytotoxicity are discussed. From the series, compound (Z)-3-methyl-6-(3,4,5-trimethoxystyryl)-2(3H)-benzothiazolone (26Z) exhibits the most potent cytotoxic activity (IC50 0.13 ± 0.01 µM) against EA.hy926 cells. 26Z not only inhibits vasculogenesis but also disrupts pre-existing vasculature. 26Z is a microtubule-modulating agent and inhibits a spectrum of angiogenic events in EA.hy926 cells by interfering with endothelial cell invasion, migration, and proliferation. 26Z also shows anti-proliferative activity in CA-4 resistant cells with the following IC50 values: HT-29 (0.008 ± 0.001 µM), MDA-MB-231 (1.35 ± 0.42 µM), and MCF-7 (2.42 ± 0.48 µM). Cell-cycle phase-specific experiments show that 26Z treatment results in G2/M arrest and mitotic spindle multipolarity, suggesting that drug-induced centrosome amplification could promote cell death. Some 26Z-treated adherent cells undergo aberrant cytokinesis, resulting in aneuploidy that perhaps contributes to drug-induced cell death. These data indicate that spindle multipolarity induction by 26Z has an exciting chemotherapeutic potential that merits further investigation.