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Tight regulatory loops orchestrate commitment to B cell fate within bone marrow. Genetic lesions in this gene regulatory network underlie the emergence of the most common childhood cancer, acute lymphoblastic leukemia (ALL). The initial genetic hits, including the common translocation that fuses ETV6 and RUNX1 genes, lead to arrested cell differentiation. Here, we aimed to characterize transcription factor activities along the B-lineage differentiation trajectory as a reference to characterize the aberrant cell states present in leukemic bone marrow, and to identify those transcription factors that maintain cancer-specific cell states for more precise therapeutic intervention.
We compared normal B-lineage differentiation and in vivo leukemic cell states using single cell RNA-sequencing (scRNA-seq) and several complementary genomics profiles. Based on statistical tools for scRNA-seq, we benchmarked a workflow to resolve transcription factor activities and gene expression distribution changes in healthy bonatory program and thereby overcome treatment resistance, we show that inhibition of ETS-transcription factors reduced cell viability and resolved pathways contributing to this using scRNA-seq.
Our data provide a detailed picture of the transcription factor activities characterizing both normal B-lineage differentiation and those acquired in leukemic bone marrow and provide a rational basis for new treatment strategies targeting the immune microenvironment and the active regulatory network in leukemia.
Our data provide a detailed picture of the transcription factor activities characterizing both normal B-lineage differentiation and those acquired in leukemic bone marrow and provide a rational basis for new treatment strategies targeting the immune microenvironment and the active regulatory network in leukemia.
Endometriosis is an estrogen-dependent inflammatory disease that often causes infertility and chronic pelvic pain. Although endometriosis is known as a benign disease, it has demonstrated characteristics of malignant neoplasms, including neoangiogenesis, tissue invasion, and cell implantation to distant organs. Octamer-binding protein 4 (Oct-4) is a molecular marker for stem cells that plays an essential role in maintaining pluripotency and self-renewal processes in various types of benign and malignant tissues. CD44 is a multifunctional cell surface adhesion molecule that acts as an integral cell membrane protein and plays a role in cell-cell and cell-matrix interactions. E-cadherin is an epithelial cell-cell adhesion molecule that plays important role in the modulation of cell polarization, cell migration, and cancer metastasis. The aim of this study was to investigate the expression patterns of Oct-4, CD44, and E-cadherin in eutopic and ectopic endometrial tissues from women with endometrioma compared toritoneal endometriotic lesions (p = 0.0304) while E-cadherin expression was negatively correlated with the presence of deep infiltrating endometriosis (p = 0.0445).
Increased expression of Oct-4 and decreased expression of adhesion molecules in endometriotic tissues may contribute to the development and progression of endometriosis.
Increased expression of Oct-4 and decreased expression of adhesion molecules in endometriotic tissues may contribute to the development and progression of endometriosis.
Considering that clinical trial studies are limited in polycystic ovary syndrome (PCOS) patients, and there is no consensus on an optimum endometrial preparation protocol for frozen embryo transfer (FET), the present study was designed as a randomized clinical trial to compare the reproductive outcomes following stimulated cycles with letrozole plus human menopausal gonadotropin (HMG) for endometrial preparation compared with routine AC-FET.
This randomized controlled trial was carried out on infertile PCOS patients who underwent IVF/ICSI and FET cycles in Arash Women's Hospital affiliated to Tehran University of Medical Sciences between September 2018 and January 2020. PCOS diagnosis was based on the Rotterdam criteria. Eligible patients were randomly allocated into two groups stimulated cycle with letrozole plus (HMG) (intervention group) and routine artificial hormonal endometrial preparation (control group).
One hundred seventy-seven infertile patients were recruited for participation in the study. re in light of current evidence, and future randomized clinical trials with larger sample sizes are required for widespread application.
The study was also registered in the Iranian Registry of Clinical Trials on March 20th, 2020. ( IRCT20090526001952N12 at www.irct.ir , registered retrospectively).
The study was also registered in the Iranian Registry of Clinical Trials on March 20th, 2020. ( IRCT20090526001952N12 at www.irct.ir , registered retrospectively).
In mammals, it is known that the estradiol-17β (E2) is mainly synthetized in ovarian granulosa cells (GCs), and the excessive apoptosis of GCs induces the follicular atresia. Many studies have implicated the essential role of KISS1, with the pro-synthetic effect of E2 and the anti-apoptotic effect on GCs, in the mammalian folliculogenesis, and several STAT4 potential binding sites were previously predicted on the promoter of KISS1 in pigs. However, the biological effects of STAT4 on GCs and the molecular regulation between STAT4 and KISS1 remained largely unknown.
Using the porcine GCs as the cellular model, the overexpression plasmid, small interfering RNA, 5'-deletion and luciferase assay were applied to investigate the molecular mechanisms for STAT4 regulating the expression of KISS1.
In this study, the STAT4 negatively regulated the mRNA and protein levels of KISS1 in porcine GCs, and the mRNA level of STAT4 was observed to significantly decrease from immature to mature follicles, which was inversed in porcine GCs. These proposed works could provide useful insight in further investigations on the molecular functionalities of STAT4 and KISS1 in the folliculogenesis of mammals.
Collectively, the STAT4 might directly target at - 305/- 295 region of KISS1 to negatively regulate the transcription of KISS1, promote the cell apoptosis via PI3K signaling pathway, suppress the synthesis of E2 through the estrogen signaling pathway in porcine GCs. click here These proposed works could provide useful insight in further investigations on the molecular functionalities of STAT4 and KISS1 in the folliculogenesis of mammals.
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