Thoughts on the Etiology of Cherubism.

Cherubism is nowadays classified as an autoimmune disease and was first described in 1933. Although suspected at that time to be the result of defective tooth development, it was primarily classified as a bone disease caused by a mutation in the SH3BP2 gene. Despite a knock-in mouse model, phenotypic signs in the jaw area were not reproducible in this model. The features of classical cherubism can be attributed to a disturbed formation of the dental placode of the second molar. Since 2019, it has become clear that inhibition of the WNT pathway leads to the accumulation of SH3BP2 via tankyrase inhibition. As the dental placode is triggered via WNT (in epithelia) and MSX1 (in mesenchyme), aplasia of the second and third molars occurs due to a block in the WNT pathway. The mesenchymal part, which occurs prior to the body plan regulation of the WNT/MSX1 pathway, remains unaffected and provides the substrate for the giant cell granuloma. Considering macrophage polarization and the role of the extracellular matrix in general, cherubism is situated in the field of tension between autoimmune diseases and cancer. In this sense, we see the cause of cherubism in a WNT-related dysregulation, which can be proven postnatally in the neural crest-related tooth development of the replacement tooth ridge, both genotypically and phenotypically.

Effect of MSX1 on the cellular function of cardiomyocytes.

MSX1 (Muscle Segment Homeobox 1) has pleiotropic effects in various tissues, including cardiomyocytes, while the effect of MSX1 on cardiomyocyte cellular function was not well known. In this study, we used AC16 cell culture, real-time fluorescence quantitative PCR (qPCR), protein blotting (Western blot), flow cytometry apoptosis assay and lactate dehydrogenase (LDH) ELISA (Enzyme-Linked Immunosorbnent Assay) to investigate the effect of the MSX1 gene on cardiomyocyte function. The results showed that MSX1 plays a protective role against hypoxia of cardiomyocytes. However, further studies are required to fully understand the role of MSX1 in the regulation of LDH expression in different cell types and under different conditions.

MSX1+PDGFRAlow limb mesenchyme-like cells as an efficient stem cell source for human cartilage regeneration.

Degenerative bone disorders have a significant impact on global health, and regeneration of articular cartilage remains a challenge. Existing cell therapies using mesenchymal stromal cells (MSCs) have shown limited efficacy, highlighting the necessity for alternative stem cell sources. Here, we have identified and characterized MSX1+ mesenchymal progenitor cells in the developing limb bud with remarkable osteochondral-regenerative and microenvironment-adaptive capabilities. Single-cell sequencing further revealed the presence of two major cell compositions within the MSX1+ cells, where a distinct PDGFRAlow subset retained the strongest osteochondral competency and could efficiently regenerate articular cartilage in vivo. Furthermore, a strategy was developed to generate MSX1+PDGFRAlow limb mesenchyme-like (LML) cells from human pluripotent stem cells that closely resembled their mouse counterparts, which were bipotential in vitro and could directly regenerate damaged cartilage in a mouse injury model. Together, our results indicated that MSX1+PDGFRAlow LML cells might be a prominent stem cell source for human cartilage regeneration.

Characterization of novel MSX1 variants causally associated with non-syndromic oligodontia in Chinese families.

BACKGROUND: MSX1 (OMIM #142983) is crucial to normal dental development, and variants in MSX1 are associated with dental anomalies. The objective of this study was to characterize the pathogenicity of novel MSX1 variants in Chinese families with non-syndromic oligodontia (NSO). METHODS: Genomic DNA was extracted from individuals representing 35 families with non-syndromic oligodontia and was analyzed by Sanger sequencing and whole-exome sequencing. Pathogenic variants were screened via analyses involving PolyPhen-2, Sorting-Intolerant from Tolerant, and MutationTaster, and conservative analysis of variants. Patterns of MSX1-related NSO were analyzed. MSX1 structural changes suggested functional consequences in vitro. RESULTS: Three previously unreported MSX1 heterozygous variants were identified: one insertion variant (c.576_577insTAG; p.Gln193*) and two missense variants (c. 871T>C; p.Tyr291His and c. 644A>C; p.Gln215Pro). Immunofluorescence analysis revealed abnormal subcellular localization of the p.Gln193* MSX1 variant. In addition, we found that these MSX1 variants likely lead to the loss of second premolars. CONCLUSION: Three novel MSX1 variants were identified in Chinese Han families with NSO, expanding the MSX1 variant spectrum and presenting a genetic origin for the pathogenesis detected in patients and their families.

MSX1 Gene Polymorphisms in Patients with non-Syndromic Cleft lip and Palate: A Tertiary Care Centre Based Case-Control Study from Central Kerala.

OBJECTIVE: The purpose of this study was to investigate the contribution of MSX1 gene polymorphisms to the risk of developing NSCLP. DESIGN: Case-Control Study. SETTING: A tertiary care centre. PATIENTS/PARTICIPANTS: The sample consisted of 200 subjects (100 cases and 100 controls). INTERVENTIONS: None. MAIN OUTCOME MEASURE(S): Genotyping was performed by restriction fragment length polymorphism. Allele and genotype frequencies were calculated between patients and controls and analyzed using online Web Tools such as SISA and SNPstats. The MSX1 gene polymorphisms c. 799 GT, c.458 CA can be risk factors in the development of orofacial clefts. RESULTS: In the cases, an association was found between NSCLP and c.799 and c.458 of the MSX1 gene when compared with the control. The dominant and overdominant models, c. 799 GT, c.458 CA genotypes and c. 799 T, c.458 A alleles in the population are said to be the main risk factors to develop the NSCLP in our study population. The genotype variation of c 799 G/T and c.458 C/A are revealed to be specifically contributing to an NSCLP-type Cleft lip and Palate. It is worth noting that NSCLP females in the study population showed a stronger association with heterozygous genotypes of c.799 and c.458. However, further investigation with a larger cohort is necessary to confirm these findings. CONCLUSION: Overall the results of the study revealed that MSX1 c 799 G > T and c.458 C > A can be considered as one of the genetic risk factors in the formation of Non-Syndromic Cleft Lip and Palate in the study population.

Genetic Factors of Teeth Impaction: Polymorphic and Haplotype Variants of PAX9, MSX1, AXIN2, and IRF6 Genes.

In recent research, there has been a growing awareness of the role of genetic factors in the positioning and eruption of teeth in the maxilla and mandible. This study aimed to evaluate the potential of specific polymorphic markers of single nucleotide polymorphisms (SNPs) located within the PAX9, MSX1, AXIN2, and IRF6 genes to determine the predisposition to tooth impaction. The study participants were divided into two groups: the first group consisted of individuals with at least one impacted secondary tooth. In contrast, the second group (control group) had no impacted teeth in their jaws. To analyze the genes, real-time PCR (polymerase chain reaction) and TaqMan probes were utilized to detect the selected polymorphisms. The findings suggest that disruptions in the structure and function of the mentioned genetic factors such as polymorphic and haplotype variants of PAX9, MSX1, AXIN2, and IRF6 genes, which play a direct role in tooth and periodontal tissue development, might be significant factors in tooth impaction in individuals with genetic variations. Therefore, it is reasonable to hypothesize that tooth impaction may be influenced, at least in part, by the presence of specific genetic markers, including different allelic variants of the PAX9, AXIN2, and IRF6 genes, and especially MSX1.

Association of MSX1 Gene Variants with Nonsyndromic Cleft Lip and/or Palate in the Pakistani Population.

OBJECTIVES: This study investigated the association of MSX1 gene variants rs3821949 and rs12532 with nonsyndromic cleft lip and/or palate (NSCL/P) in the Pakistani population. DESIGN: Comparative cross-sectional study.Setting: Multicenter of CL/P malformation.Patients/Participants: Unrelated Non-Syndromic cleft Lip/Palate patients and healthy controls were enrolled. METHODS: One hundred (n = 100) subjects with NSCL/P and n = 50 unrelated healthy controls were enrolled in a multicenter comparative cross-sectional study. A tetra amplification refractory mutation system (ARMS) polymerase chain reaction (PCR) was performed to analyze MSXI gene single nucleotide variants (SNVs). RESULTS: Among 100 NSCL/P subjects, the majority were males (56%; male: female = 1.27: 1). Most of the cases (74%) had cleft lip and palate (CLP) compared to isolated clefts. Genotyping of MSX1 gene variant rs3821949 showed an increased risk for NSCL/P in various genetic models (P < 0.0001), and the A allele exhibited a more than 4-fold increased risk among cases (OR = 4.22: 95% CI = 2.16-8.22; P < 0.0001). Our investigation found no significant difference between the rs12532 variation and NSCL/P. CONCLUSION: Our study findings suggest that MSX1 gene variants may increase predisposition to NSCL/P in the Pakistani population. Further studies comprising large samples are required to identify the genetic aetiology of NSCL/P among our people.

Non-syndromic Oligodontia in Primary Dentition: A Report of a Rare Case.

The congenital absence of teeth is the most common dental anomaly affecting 2.2% to 10% of the population. It could be present in the form of anodontia, hypodontia, or oligodontia, excluding wisdom teeth. Oligodontia is most commonly associated with several syndromes like ectodermal dysplasia, Down syndrome, and Van der Woude syndrome that involve the mutation of the MSX-1 and PAX-1 genes. Few cases have been reported in the literature on how oligodontia affects primary dentition. In this case report, a total of 17 primary teeth were missing. This case report investigates whether the features of non-syndromic oligodontia are present in the primary dentition in a two-year-old boy.

MSX1-expression during the different phases in healthy human endometrium.

PURPOSE: The human endometrium consists of different layers (basalis and functionalis) and undergoes different phases throughout the menstrual cycle. In a former paper, our research group was able to describe MSX1 as a positive prognosticator in endometrial carcinomas. The aim of this study was to examine the MSX1 expression in healthy endometrial tissue throughout the different phases to gain more insight on the mechanics of MSX-regulation in the female reproductive system. MATERIALS AND METHODS: In this retrospective study, we investigated a total of 17 normal endometrial tissues (six during proliferative phase and five during early and six during late secretory phase). We used immunohistochemical staining and an immunoreactive score (IRS) to evaluate MSX1 expression. We also investigated correlations with other proteins, that have already been examined in our research group using the same patient collective. RESULTS: MSX1 is expressed in glandular cells during the proliferative phase and downregulated at early and late secretory phase (p = 0.011). Also, a positive correlation between MSX1 and the progesterone-receptor A (PR-A) (correlation coefficient (cc) = 0.0671; p = 0.024), and the progesterone receptor B (PR-B) (cc = 0.0691; p = 0.018) was found. A trend towards negative correlation was recognized between MSX1 and Inhibin Beta-C-expression in glandular cells (cc = - 0.583; p-value = 0.060). CONCLUSION: MSX1 is known as a member of the muscle segment homeobox gene family. MSX1 is a p53-interacting protein and overexpression of homeobox MSX1 induced apoptosis of cancer cells. Here we show that MSX1 is expressed especially in the proliferative phase of glandular epithelial tissue of the normal endometrium. The found positive correlation between MSX1 and progesterone receptors A and B confirms the results of a previous study on cancer tissue by our research group. Because MSX1 is known to be downregulated by progesterone, the found correlation of MSX1 and both PR-A and -B may represent a direct regulation of the MSX1 gene by a PR-response element. Here further investigation would be of interest.

A single-cell census of mouse limb development identifies complex spatiotemporal dynamics of skeleton formation.

Limb development has long served as a model system for coordinated spatial patterning of progenitor cells. Here, we identify a population of naive limb progenitors and show that they differentiate progressively to form the skeleton in a complex, non-consecutive, three-dimensional pattern. Single-cell RNA sequencing of the developing mouse forelimb identified three progenitor states: naive, proximal, and autopodial, as well as Msx1 as a marker for the naive progenitors. In vivo lineage tracing confirmed this role and localized the naive progenitors to the outer margin of the limb, along the anterior-posterior axis. Sequential pulse-chase experiments showed that the progressive transition of Msx1+ naive progenitors into proximal and autopodial progenitors coincides with their differentiation to Sox9+ chondroprogenitors, which occurs along all the forming skeletal segments. Indeed, tracking the spatiotemporal sequence of differentiation showed that the skeleton forms progressively in a complex pattern. These findings suggest an alternative model for limb skeleton development.

MSX1 Regulates Goat Endometrial Function by Altering the Plasma Membrane Transformation of Endometrial Epithelium Cells during Early Pregnancy.

MSX1 is an important member of the muscle segment homeobox gene (Msh) family and acts as a transcription factor to regulate tissue plasticity, yet its role in goat endometrium remodeling remains elusive. In this study, an immunohistochemical analysis showed that MSX1 was mainly expressed in the luminal and glandular epithelium of goat uterus, and the MSX1 expression was upregulated in pregnancy at days 15 and 18 compared with pregnancy at day 5. In order to explore its function, goat endometrial epithelial cells (gEECs) were treated with 17 ß-estrogen (E2), progesterone (P4), and/or interferon-tau (IFNτ), which were used to mimic the physiological environment of early pregnancy. The results showed that MSX1 was significantly upregulated with E2- and P4-alone treatment, or their combined treatment, and IFNτ further enhanced its expression. The spheroid attachment and PGE2/PGF2α ratio were downregulated by the suppression of MSX1. The combination of E2, P4, and IFNτ treatment induced the plasma membrane transformation (PMT) of gEECs, which mainly showed the upregulation of N-cadherin (CDH2) and concomitant downregulation of the polarity-related genes (ZO-1, α-PKC, Par3, Lgl2, and SCRIB). The knockdown of MSX1 partly hindered the PMT induced by E2, P4, and IFNτ treatment, while the upregulation of CDH2 and the downregulation of the partly polarity-related genes were significantly enhanced when MSX1 was overexpressed. Moreover, MSX1 regulated the CDH2 expression by activating the endoplasmic reticulum (ER) stress-mediated unfolded protein response (UPR) pathway. Collectively, these results suggest that MSX1 was involved in the PMT of the gEECs through the ER stress-mediated UPR pathway, which affects endometrial adhesion and secretion function.

Genetic and Morphological Variation in Hypodontia of Maxillary Lateral Incisors.

(1) Background: Hypodontia has a multifactorial aetiology, in which genetic factors are a major component. Associated with this congenital absence, the formed teeth may show differences in size and shape, which may vary with the specific genetic variants and with the location of the missing teeth. The aims of the present study were to investigate a specific variant of MSX1, derive morphometric tooth measurements in a sample of patients with isolated maxillary lateral incisor agenesis and matched controls, and model the findings. (2) Methods: Genotyping of the MSX1 rs8670 genetic variant and morphometric measurements with a 2D image analysis method were performed for 26 hypodontia patients and 26 matched controls. (3) Results: The risk of upper lateral incisor agenesis was 6.9 times higher when the T allele was present. The morphometric parameters showed significant differences between hypodontia patients and controls and between the unilateral and bilateral agenesis cases. The most affected crown dimension in the hypodontia patients was the bucco-lingual dimension. In crown shape there was significant variation the Carabelli trait in upper first molars. (4) Conclusions: The MSX1 rs8670 variant was associated with variations in morphological outcomes. The new findings for compensatory interactions between the maxillary incisors indicate that epigenetic and environmental factors interact with this genetic variant. A single-level directional complex interactive network model incorporates the variations seen in this study.

MSX1 involved selective tooth agenesis and abnormal labial frenum, pedigree, and retrospective study.

OBJECTIVE: Muscle segment homeobox gene 1 (MSX1) is widely expressed in craniofacial development and tooth formation. The aim of this study was to report a novel MSX1 mutation in a Chinese family with selective tooth agenesis and abnormal median maxillary labial frenum (MMLF). MATERIALS AND METHODS: Mutation analysis was carried out by whole exome sequencing. The pMD18-T vector was used to verify the mutations. PubMed and Human Gene Mutation Database were searched to analyze the relationship between the mutations in MSX1 and related phenotypes. RESULTS: A novel heterozygous mutation (c.75delG) in MSX1 was detected in the proband and her mother. They presented as oligodontia and lower attached hypertrophy median maxillary labial frenum. 60 MSX1 mutations from 39 reports did not declare malformed MMLF except our cases. Meanwhile, we found that the types and sites of MSX1 mutations may affect the selectivity of tooth agenesis and orofacial cleft. CONCLUSION: This study suggests malformed MMLF as a new phenotype of MSX1 mutation and a specific relationship between MSX1 genotype and phenotype.

A novel mutation in the WNT6 gene of congenital tooth agenesis / 口腔疾病防治

Objective @#This article explores the relationship between congenital tooth agenesis and related gene mutations, providing a reference for early diagnosis of the disease.@*Methods @# Clinical and radiographic examinations of a rare case of congenital tooth agenesis were conducted to evaluate the abnormal morphology and quantity of the teeth, as well as the overall health of the patient. Bidirectional sequencing of the PAX9 and MSX1 genes and whole-exome sequencing were conducted to identify potential genetic abnormalities. Sanger sequencing of the newly discovered mutation site was performed on the proband's son. Subsequently, the impacts of the mutations were evaluated through computational tools and a cell-based gene transfection assay. @*Results @#This is a rare case of tooth agenesis characterized by a congenitally missing first molar, a second molar with one single root and a supernumerary second premolar in the right mandibular dentition. The c.717 C>C/T in PAX9 is synonymous. The c.119C>G in MSX1 is a missense mutation predicted to be “benign” by Polyphen. Through whole-exome sequencing, we found a novel mutation, c.637-7 C>A in intron 3 of the WNT6 gene, which is predicted by MAXENT to influence the splicing of mRNA. Both the proband and his son carry this mutation. A cell-based gene transfection assay demonstrated that it did not alter the mRNA splicing of WNT6. @* Conclusion @#The interaction between single nucleotide polymorphisms may contribute to congenital tooth agenesis.

Dental niche cells directly contribute to tooth reconstitution and morphogenesis.

Mammalian teeth develop from the inductive epithelial-mesenchymal interaction, an important mechanism shared by many organs. The cellular basis for such interaction remains elusive. Here, we generate a dual-fluorescence model to track and analyze dental cells from embryonic to postnatal stages, in which Pitx2+ epithelium and Msx1+ mesenchyme are sufficient for tooth reconstitution. Single-cell RNA sequencing and spatial mapping further revealed critical cellular dynamics during molar development, where tooth germs are organized by Msx1+Sdc1+ dental papilla and surrounding dental niche. Surprisingly, niche cells are more efficient in tooth reconstitution and can directly regenerate papilla cells through interaction with dental epithelium. Finally, from the dental niche, we identify a group of previously unappreciated migratory Msx1+ Sox9+ cells as the potential cell origin for dental papilla. Our results indicate that the dental niche cells directly contribute to tooth organogenesis and provide critical insights into the essential cell composition for tooth engineering.

Detection of a rare AXIN2 variant in an Iranian family with hypodontia and oligodontia.

Background. Hypodontia, or the absence of one or more teeth during tooth formation, is a highly prevalent dental anomaly. Nevertheless, the main causes are still unknown. Mutations in PAX9, MSX1, WNT10A, and AXIN2 genes are most commonly associated with non-syndromic tooth agenesis in the literature. This study investigated these candidate genes in an Iranian family with non-syndromic hypodontia and oligodontia. Methods. Peripheral blood samples of the proband and her family members were collected, and DNA extractions using the salting-out method were carried out. In addition, polymerase chain reaction (PCR) and Sanger sequencing for candidate genes were performed. Results. A missense variant (rs4904210) was identified in the PAX9 gene, with one heterozygous missense variant (rs2240308) and one stop-gained variant (rs121908568) in the AXIN2 gene. Conclusion. By surveying similar studies and analyzing the variant in bioinformatics websites, we concluded that the heterozygous stop-gained variant rs121908568 in exon 8 of the AXIN2 gene could be responsible for tooth agenesis in the Iranian population.

Detección polimórfica del rs104893850 de MSX1 y rs28933373 de PAX9 en personas con agenesia dental no sindrómica / Polymorphic detection of rs104893850 of MSX1 and rs28933373 of PAX9 in people with non syndromic dental agnesia

Introducción: la agenesia dental no sindrómica (ADNS) genera efec- tos negativos en la salud oral y psicosocial de los seres humanos. El determinante genético desempeña un papel importante en su desarrollo. Objetivo: determinar la frecuencia de los polimorfismos rs104893850 de MSX1 y rs28933373 de PAX9 en pacientes de seis a 18 años con ADNS. Material y métodos: estudio transversal prolectivo en el cual se revisaron individuos de seis a 18 años sin defectos congénitos y originarios del estado de Durango. Después de haber obtenido su con- sentimiento para formar parte del estudio, se estableció el diagnóstico de ADNS a través de una inspección clínica odontológica y un examen radiográfico. Se tomó una muestra de sangre capilar para la genotipi- ficación de los polimorfismos a través de la técnica de qPCR-HRM. Resultados: de un total de 124 individuos, 77 (62%) mujeres y 47 (38%) hombres; sólo 39 presentaron ADNS. En el análisis polimórfico de rs104893850 de MSX1 y rs28933373 de PAX9 se obtuvo 94.9% y 84.6% respectivamente de homocigotos mutados. Conclusiones: se obtuvo una alta frecuencia de hipodoncia, el diente que mostró más agenesia fue el órgano dentario 18. Las mutaciones polimórficas están presentes en una alta proporción de agenesia dental (AU)

Introduction: non-syndromic dental agenesis (NSDA) generates negative oral health and psychosocial effects in humans. The genetic determinant plays an important role in its development. Objective: to determine the frequency of MSX1 rs104893850 and PAX9 rs28933373 polymorphisms in patients aged 6 to 18 years with NSDA. Material and methods: prolective cross-sectional study, in which individuals aged 6 to 18 years without congenital defects and from the city of Durango were reviewed. After obtaining their consent to be part of the study, the diagnosis of NSDA was established through a clinical dental inspection, a radiographic examination and a capillary blood sample was taken for the genotyping of the polymorphisms through the qPCR-HRM technique. Results: out of a total of 124 individuals, 77 (62%) females and 47 (38%) males; only 39 presented ADNS. In the polymorphic analysis of rs104893850 of MSX1 and rs28933373 of PAX9 we obtained 94.9% and 84.6% respectively of mutated homozygotes. Conclusions: a high frequency of hypodontia was obtained, and the tooth that presented the most agenesis was dental organ 18. Polymorphic mutations are present in a high proportion for dental agenesis (AU)

Expression of Cell Cycle Markers and Proliferation Factors during Human Eye Embryogenesis and Tumorigenesis.

The expression pattern of the markers p19, Ki-67, MSX1, MSX2, PDL1, pRB, and CYCLINA2 was quantitatively and semiquantitatively analyzed in histologic sections of the developing and postnatal human eye at week 8, in retinoblastoma, and in various uveal melanomas post hoc studies by double immunofluorescence. The p19 immunoreactivity characterized retinal and/or choroidal cells in healthy and tumor tissues: expression was lower in the postnatal retina than in the developing retina and retinoblastoma, whereas it was high in epithelioid melanomas. Ki67 expression was high in the developing eye, retinoblastoma, and choroidal melanomas. MSX1 and MSX2 expression was similar in the developing eye and retinoblastoma, whereas it was absent in the postnatal eye. Their different expression was evident between epithelioid and myxoid melanomas. Similarly, PDL1 was absent in epithelioid melanomas, whereas it was highly expressed in developing and tumor tissues. Expression of pRB and CYCA2 was characteristic of developing and tumorous eye samples but not of the healthy postnatal eye. The observed expression differences of the analyzed markers correlate with the origin and stage of cell differentiation of the tissue samples. The fine balance of expression could play a role in both human eye development and ocular tumorigenesis. Therefore, understanding their relationship and interplay could open new avenues for potential therapeutic interventions and a better understanding of the mechanisms underlying the developmental plasticity of the eye and the development of neoplasms.

A single-nucleotide-polymorphism in the 5'-flanking region of MSX1 gene as a predictive marker candidate for platinum-based therapy of esophageal carcinoma.

BACKGROUND: Platinum derivatives are important treatment options for patients with esophageal carcinoma (EC), and a predictive marker for platinum-based therapy is needed for precision medicine. PATIENTS AND METHODS: This study contained two cohorts consisting of EC patients treated using platinum-based chemoradiation therapy (CRT) as the first-line and another external cohort of nationwide clinicogenomic data from the BioBank Japan (BBJ). RESULTS: Genome-wide association study (GWAS) of therapeutic outcomes, refractory disease or not, following platinum-based CRT as first-line in 94 patients in the first cohort suggested the association of 89 SNPs using p < 0.0001. The top 10 SNPs selected from each chromosomal region by odds ratio were evaluated for progression-free survival (PFS) and overall survival (OS) hazard ratios in the first cohort, resulting in four candidates (p < 0.0025). The four selected candidates were re-evaluated in another cohort of 24 EC patients, which included patients prospectively enrolled in this study to fulfill the sample size statistically suggested by the results of the first cohort, and of the four, only rs3815544 was replicated (p < 0.0125). Furthermore, this candidate genotype of rs3815544 proceeded to the re-evaluation study in an external cohort consisting of EC patients treated with platinum derivatives and/or by radiation therapy as the first-line treatment in BBJ, which confirmed that the alternative allele (G) of rs3815544 was statistically associated with non-response (SD or PD) to platinum-based therapy in EC patients (odds ratio = 1.801, p = 0.048). The methylation QTL database as well as online clinicogenomic databases suggested that the region including rs3815544 may regulate MSX1 expression through CpG methylation, and this down-regulation was statistically associated with poor prognosis after platinum-based therapies for EC. CONCLUSION: rs3815544 is a novel candidate predictive marker for platinum-based EC therapy.

The effect of dexamethasone on uterine receptivity, mediated by the ERK1/2-mTOR pathway, and the implantation window: An experimental study.

Background: The role of glucocorticoids in implantation has been demonstrated. Objective: This study aimed to evaluate the effect of dexamethasone on endometrial receptivity. Materials and Methods: In this experimental study, 40 BALB/c female mice aged eight wk old weighing approximately 25.0 ± 1.4 gr were used. The mice were divided into four groups (n = 10/each) of control, dexamethasone (100 µg/kg, intraperitoneal injection), mammalian target of rapamycin (mTOR) inhibitor (PP242) (30 mg/kg, intraperitoneal injection), and dexamethasone and PP242. The endometrial epithelium of the mouse was separated to measure messenger RNA expression of heart and neural crest derivatives-expressed protein 2 (HAND2), Msh homeobox 1 (Msx-1), heparin binding epidermal growth factor (HB-EGF), microRNA (miRNA) Let-7a, miRNA-145 and miRNA-451, using real-time polymerase chain reaction. Also, protein expression of mammalian mTOR and eukaryotic translation initiation factor 4E-binding protein1 (4E-BP1) was measured using western blot. Results: The results revealed that the expression of Msx-1, HAND2, HB-EGF, miRNA-451, and miRNA-Let-7a was significantly decreased in the endometrium in the dexamethasone group compared to the control, while the expression of miRNA-145 in the endometrium was up-regulated. Additionally, the administration of PP242, known as an inhibitor of mTOR, was associated with significantly reduced expression of Msx-1, HAND2, HB-EGF, miRNA-451, and miRNA-Let-7a, while PP242 induced messenger RNA expression of miRNA-145. Conclusion: It appears that dexamethasone can diminish uterine receptivity during the implantation period, at least to some extent, through the alteration of particular genes that impact endometrial receptivity. Furthermore, the mTOR pathway seemingly showed an essential role in endometrial receptivity.