A thinner endometrium is associated with lower newborn birth weight during in vitro fertilization-frozen-embryo transfer: a cohort study.

PURPOSE: This study explores the effects of endometrial thickness (EMT) before embryo transfer on newborn birth weight after in vitro fertilization-frozen embryo transfer (IVF-FET). METHODS: We collected the medical records related to singleton live births after IVF-FET from June 2015 to February 2019. Pregnant women were aged ≤ 42 years at delivery. Afterward, analyses were performed on outcomes related to newborns (birth weight, gestational age, delivery mode, percentage of newborns with low birth weight, and incidence of macrosomia) and pregnant women (pregnancy-induced hypertension, gestational diabetes mellitus, premature rupture of membranes, and placenta previa). RESULTS: The birth weight was higher in singleton newborns delivered by patients with EMT > 12 mm before embryo transfer than those delivered by patients with a thinner endometrium. The mean birth weight was 85.107 g higher in the EMT ≥ 12 mm group and 25.942 g higher in the 8-12 mm EMT group than in the EMT < 8 mm group. Independent predictors of newborn birth weight included pregnancy-induced hypertension, premature rupture of membranes, placenta previa, newborn sex, gestational age, delivery mode, number of implanted embryos, follicle-stimulating hormone levels, estradiol levels, and pre-pregnancy body mass index. CONCLUSION: The weight of newborn singletons is associated with EMT before embryo transfer in patients undergoing the first FET cycle. Specifically, the birth weight is lower for newborns delivered by patients with a thinner endometrium. Accordingly, it is warranted to increase EMT before embryo transfer for improving neonatal outcomes after fertility treatment.

Molecular mechanisms and differences in lynch syndrome developing into colorectal cancer and endometrial cancer based on gene expression, methylation, and mutation analysis.

PURPOSE: The aim of this study was to screen biomarkers specific to Lynch syndrome (LS) with colorectal cancer (CRC) or endometrial cancer (EC) to explore the mechanisms by which LS develops into CRC and EC and their differences. METHODS: Differentially expressed or differentially methylated genes and differential mutations were identified in 10 LS, 50 CRC, and 50 EC patients from TCGA, and genes overlapping between LS and CRC or EC (named SGs-LCs and SGs-LEs, respectively) were identified. Afterward, we annotated the enriched GO terms and pathways and constructed a protein-protein interaction (PPI) network. Finally, samples from 10 clinical cases with MSI-H/MSS CRC and EC were collected to verify the mutations and their correlations with five LS pathogenic genes in the SGs-LCs and SGs-LEs. RESULTS: A total of 494 SGs-LCs and 104 SGs-LEs were identified and enriched in 106 and 14 GO terms, respectively. There were great differences in the gene count and enriched terms between SGs-LCs and SGs-LEs. In the PPI network, SST, GCG, SNAP25, and NPY had the highest degree of connection among the SGs-LCs, and KIF20A and NUF2 had the highest degree of connection among the SGs-LE. In the SGs-LCs and SGs-LEs, the genes whose expression levels affected the survival of LS, CRC or EC patients were quite different. CONCLUSIONS: COL11A1 was found to be mutated in MSS CRC patients, similar to the mutations of MSH6. SST, GCG, SNAP25, and NPY may be biomarkers for the development of LS into CRC, and KIF20A and NUF2 may be markers of LS developing into EC.

Circ_0039569 contributes to the paclitaxel resistance of endometrial cancer via targeting miR-1271-5p/PHF6 pathway.

Circular RNA (circRNA) has been confirmed to be involved in the chemoresistance process of cancers. However, whether circ_0039569 mediates the chemoresistance of endometrial cancer (EC) remains unclear. Quantitative real-time PCR was performed to analyze circ_0039569, microRNA (miR)-1271-5p and PHD finger protein 6 (PHF6) expression. Cell counting kit-8 assay was used to assess the paclitaxel (PTX) resistance of cells. Cell proliferation, apoptosis and invasion were determined using EdU assay, colony formation assay, flow cytometry and transwell assay. Protein expression was examined by western blot analysis. RNA interaction was verified by dual-luciferase reporter assay and RNA pull-down assay. Xenograft tumor models were constructed to explore the effect of circ_0039569 knockdown on the PTX sensitivity of EC tumors. Circ_0039569 was upregulated in PTX-resistant EC tissues and cells. Knockdown of circ_0039569 enhanced the PTX sensitivity of EC cells by inhibiting cell growth and invasion. MiR-1271-5p could be sponged by circ_0039569, and its inhibitor abolished the regulation of circ_0039569 knockdown on the PTX sensitivity of EC cells. PHF6 was targeted by miR-1271-5p, and its overexpression eliminated the promotion effect of miR-1271-5p on the PTX sensitivity of EC cells. Also, interference of circ_0036569 enhanced the PTX sensitivity of EC tumors by regulating the miR-1271-5p/PHF6 pathway. Collectively, circ_0039569 might contribute to the PTX resistance of EC through the regulation of the miR-1271-5p/PHF6 axis.

Clinical manifestations and prognosis of unexpected uterine sarcoma of uterine fibroids in Tianjin China.

BACKGROUND: Uterine sarcoma is a rare malignancy of women and fewer uterine sarcomas are detected preoperatively. The reported incidence of preoperatively diagnosed uterine sarcoma (PDUS) was 0.07%. This study aims to identify the prevalence of unexpected uterine sarcoma (UUS) after operation for presumed leiomyoma and compare clinical outcomes after primary therapy. METHODS: A retrospective study was performed evaluating all uterine sarcoma diagnosed in Tianjin Central Hospital of Gynecology and Obstetrics between May 2011 and July 2016.We used the χ2 and T tests to assess the incidence and clinical features of patients. The Kaplan-Meier method was used to calculate disease-related survival. RESULTS: The study retrospectively analyzed 6625 patients with uterine fibroids and found 45 UUS patients and 21 patients of PDUS. The incidence of UUS is (45/6625) 0.67%. The incidence of UUS in patients undergoing total hysterectomy was higher undergoing tumor resection (P < 0.001); the age of UUS is younger than PDUS (P = 0.046); the differences in menopausal status and primary complaints between the two groups are not statistically significant. The PDUS group had more patients with Stage II and III sarcomas than the UUS group (P < 0.001); the duration of symptoms in the PDUS group was longer than in the UUS group (P = 0.033). The 5-year overall survival (OS) rate of the UUS group (77.7%) is higher than the PDUS group (46.3%) (P < 0.001). CONCLUSIONS: The incidence of UUS is low. UUS has a younger age of onset, shorter history of the disease, earlier clinical stage, and better prognosis.

DNA methylation markers as triage test for the early identification of cervical lesions in a Chinese population.

Objective strategies are required in cervical cancer screening. We have identified several DNA methylation markers with high sensitivity and specificity to detect cervical intraepithelial neoplasia 2 or worse (CIN2+) in Dutch women. Our study aims to analyze the diagnostic characteristics of these markers in a Chinese cohort. A total of 246 liquid-based cytology samples were included, of which 205 women underwent colposcopy due to an abnormal cytology result (atypical squamous cells of undetermined significance [ASCUS] or worse), while 227 were tested high-risk human papillomavirus (hrHPV) positive. All six individual markers (ANKRD18CP, C13ORF18, EPB41L3, JAM3, SOX1 and ZSCAN1) showed enhanced methylation levels and frequency with increasing severity of the underlying lesion (P ≤ .001). In cytological abnormal women, sensitivity to detect CIN2+ was 79%, 76% and 72% for the three panels (C13ORF18/EBP41L3/JAM3, C13ORF18/ANKRD18CP/JAM3 and ZSCAN1/SOX1, respectively), with a specificity of 57%, 65% and 68%. For the first two panels, these diagnostic characteristics were similar to the Dutch cohort, while for ZSCAN1/SOX1 the sensitivity was higher in the Chinese cohort, but with a lower specificity (both P < .05). In hrHPV-positive samples, similar sensitivity and specificity for the detection of CIN2+ were found as for the abnormal cytology cohort, which were now all similar between both cohorts and non-inferior to HPV16/18 genotyping. Our analysis reveals that the diagnostic performances are highly comparable for C13ORF18/EBP41L3/JAM3 and C13ORF18/ANKRD18CP/JAM3 methylation marker panels in both Chinese and Dutch cohorts. In conclusion, methylation panels identified in a Dutch population are also applicable for triage testing in cervical cancer screening in China.

Cytogenetic Analysis of the Products of Conception After Spontaneous Abortion in the First Trimester.

In the present study, we retrospectively recruited 340 patients who underwent spontaneous abortions to investigate chromosomal abnormalities of the conception products in the first trimester. We also performed a relevant analysis of clinical factors. Of these patients, 165 had conception products with chromosomal abnormalities, including 135 aneuploidies, 11 triploidies, 10 complex abnormalities, and 9 segmental aneuploidies. The most common abnormal chromosomes were chromosome 16 in the embryo-transfer group and sex chromosomes in the natural-conception group. The most common abnormal chromosomes in all analyzed maternal age groups were sex chromosomes, 16, and 22. The chromosomal abnormality incidence was related to age and number of spontaneous abortions (both p < 0.05), but not to number of pregnancies, deliveries, induced abortions, or methods of conception (all p > 0.05). The rates of abnormality for chromosomes 12, 15, 20, and 22 increased with age, while the rates for chromosomes 6, 7, 13, and X decreased. In all age groups, aneuploidy was by far the most common abnormality; however, the low-incidence distributions of chromosomal abnormalities were entirely different. Overall, chromosomal aneuploidy was the primary cause of pregnancy loss in the first trimester, and low-frequency abnormalities differed across age subgroups. Chromosomal aberrations were found to be related to maternal age and spontaneous abortion, but not all chromosomal abnormalities increased with age.

Multi gene mutation signatures in colorectal cancer patients: predict for the diagnosis, pathological classification, staging and prognosis.

BACKGROUND: Identifying gene mutation signatures will enable a better understanding for the occurrence and development of colorectal cancer (CRC), and provide some potential biomarkers for clinical practice. Currently, however, there is still few effective biomarkers for early diagnosis and prognostic judgment in CRC patients. The purpose was to identify novel mutation signatures for the diagnosis and prognosis of CRC. METHODS: Clinical information of 531 CRC patients and their sequencing data were downloaded from TCGA database (training group), and 53 clinical patients were collected and sequenced with targeted next generation sequencing (NGS) technology (validation group). The relationship between the mutation genes and the diagnosis, pathological type, stage and prognosis of CRC were compared to construct signatures for CRC, and then analyzed their relationship with RNA expression, immunocyte infiltration and tumor microenvironment (TME). RESULTS: Mutations of TP53, APC, KRAS, BRAF and ATM covered 97.55% of TCGA population and 83.02% validation patients. Moreover, 57.14% validation samples and 22.06% TCGA samples indicated that patients with mucinous adenocarcinoma tended to have BRAF mutation, but no TP53 mutation. Mutations of TP53, PIK3CA, FAT4, FMN2 and TRRAP had a remarkable difference between I-II and III-IV stage patients (P < 0.0001). Besides, the combination of PIK3CA, LRP1B, FAT4 and ROS1 formed signatures for the prognosis and survival of CRC patients. The mutations of TP53, APC, KRAS, BRAF, ATM, PIK3CA, FAT4, FMN2, TRRAP, LRP1B, and ROS1 formed the signatures for predicting diagnosis and prognosis of CRC. Among them, mutation of TP53, APC, KRAS, BRAF, ATM, PIK3CA, FAT4 and TRRAP significantly reduced their RNA expression level. Stromal score, immune score and ESTIMATE score were lower in patients with TP53, APC, KRAS, PIK3CA mutation compared non-mutation patients. All the 11 gene mutations affected the distributions of immune cells. CONCLUSION: This study constructed gene mutation signatures for the diagnosis, treatment and prognosis in CRC, and proved that their mutations affected RNA expression levels, TME and immunocyte infiltration. Our results put forward further insights into the genotype of CRC.

Pregnancy outcomes of infertile women with ultrasound-diagnosed adenomyosis for in vitro fertilization and frozen-thawed embryo transfer.

OBJECTIVE: This study aimed to investigate the effect of ultrasound-diagnosed adenomyosis on assisted pregnancy outcomes, i.e., in vitro fertilization-embryo transfer (IVF-ET). METHODS: This was a retrospective cohort study of 18,568 women who had received their first frozen-thawed ET cycle in Center of Reproductive Medicine, Children's Hospital of Shanxi and Women Health Center of Shanxi and the Reproductive Medicine Center of Tianjin Central Obstetrics and Gynecology Hospital from January 2014 to May 2019. A total of 5,087 patients met the inclusion and exclusion criteria, and they were divided into two groups: adenomyosis with tubal factor infertility (study group, n = 193) and only tubal factor infertility (control group, n = 4894). After a 1:1 propensity score match (caliper value = 0.005), 360 cases were matched in the end. RESULT: There was no statistical difference in the embryo implantation rate, clinical pregnancy rate, or multiple pregnancy rate between the two groups (28.4% vs. 31.7%, 42.2% vs. 42.8%, and 11.7% vs. 12.8%, respectively; P > 0.05). However, the early miscarriage rate in the adenomyosis group was significantly higher than that in the control group (13.3% vs. 5.6%, respectively; P = 0.012). The live birth rate was 22.8% in the women with adenomyosis and was observed to be significantly lower than 33.3% in the control group (P = 0.026). The patients with adenomyosis had a higher incidence of pregnancy complications than those without (4.4% vs. 0.6%, respectively; P = 0.018), but the neonatal birth weight was not related to adenomyosis. CONCLUSION: Women with adenomyosis should be treated as being at high risk of early miscarriage. However, maternal adenomyosis has no effect on the birth weight of the newborn.

A retrospective validation study of sentinel lymph node mapping for high-risk endometrial cancer.

OBJECTIVES: To determine the feasibility and performance of sentinel lymph-node (SLN) mapping among women with high-risk endometrial cancer (EC). MATERIALS AND METHODS: Ninety-eight patients at high-risk EC were enrolled in this retrospective surgical trial from August 2016 to August 2018. All patients underwent intraoperative SLN biopsy, with ICG injection for laparoscopic staging; this was followed by pelvic and paraaortic lymphadenectomy (LAD). Outcomes included SLN detection rate, false-negative SLN algorithm rate, and the negative predictive value (NPV) of the SLN algorithm. The Chi-square test was used to analyze the relationship between SLN mapping and the risk factors. Then, we performed Kappa consistency check (P < 0.05 with Meaning), to estimate the consistency of SLN and lymph-node metastasis. RESULTS: Successful biopsy occurred in 94 patients (170 sides) among 98 patients (196 sides). At least 1 SLN was identified in 86.7% (170/196). Overall, the false-negative rate (FNR) was 11.8% (2/17), NPV was 97.3% (72/74), and sensitivity was 88.2% (15/17). 22/98 patients (22.4%) with high-risk EC had at least one metastatic lymph node identified. When the SLN algorithm was retrospectively applied, the FNR was 9.1% (2/22) and sensitivity was 90.9% (20/22). Considering the surgeon's experience, 68 cases of EC (except for 30 patients), the detection rate was 89.7% (122/136), NPV was 98.1% (50/51), and the FNR was 5.6% (1/18). The factor significantly affecting the detection rate of SLNs was lymphovascular space invasion (LVSI) (P = 0.016). SLN metastasis of EC was associated with depth of myometrial invasion (P = 0.034). The analysis result of SLN and the consistency of pelvic lymph-node metastasis status. As detected by Kappa coefficient was 0.939 (P < 0.001), suggests highly consistency. CONCLUSIONS: Our SLN detection rate for high-risk EC was the same as previously reported. When SLN is not detected, better after 30 patients' experience, is a reasonable alternative to complete LAD in high-risk EC. In addition, SLN shows high co-occurrence with pelvic lymph nodes. Therefore, SLN biopsy can be used to diagnose high-risk EC.

A prospective study on the predictive value of DNA methylation in cervical intraepithelial neoplasia prognosis.

PURPOSE: To study the predictive value of the DNA methylation levels of JAM3, SOX1, SLIT2, C13ORF18, and TERT in the cervical intraepithelial neoplasia prognosis. METHOD: In the present study, 139 cases were collected and followed up for 24 months. The DNA methylation levels of JAM3, SOX1, SLIT2, C13ORF18, and TERT were tested from their exfoliated cells. One-way ANOVA, receiver operating characteristic (ROC) curve analyses were conducted to analyze the data. RESULTS: The DNA methylation of the five genes was associated with prognosis of CIN. The levels of methylation increased as the progression of lesion for the prognosis. For CIN1, difference between DNA methylation of JAM3, SOX1, SLIT2, and C13ORF18 had significance statistically (P < 0.001). Sensitivity (95.2%) and specificity (93.1%) of JAM3 were the highest compared with other genes for the prognosis of CIN1. In addition, for CIN2/3, DNA methylation of JAM3, SOX1, SLIT2, TERT, and C13ORF18 had difference statistically (P < 0.001). JAM3 were also the highest in sensitivity (95.2%) and specificity (93.1%) compared with other genes for the prognosis of CIN2/3. CONCLUSIONS: Our data suggest for the first time that DNA methylation levels are associated with prognosis of CIN significantly. DNA methylation levels of some genes, especially JAM3, may serve as markers for the prediction of the CIN prognosis, including CIN1 nature prognosis and CIN2/3 after treatment.

[Relationship between the methylation of L1 3' and long control region gene of HPV16 DNA and it's pathogenicity].

OBJECTIVE: Quantifiably and located measure the methylation rate of 21 cytosine-phosphate-guanosine (CpG) sites in the 3' region of L1 gene and long control region (LCR) gene of HPV16 DNA in asymptomatic patients, cervical intraepithelial neoplasia (CIN) patients, and cervical cancer patients. To analysis the relationship between HPV16 methylation and it's pathogenicity. METHODS: Chosen 30 cases with HPV16 positive in each group. Firstly, extract DNA from the remaining cells of liquid-based cytology specimen and bisulfite treatment DNA, then amplify the 3' region of L1 gene and LCR gene, test the methylation rate of 21 CpG sites of HPV16 DNA in three groups. RESULTS: All of the 5 CpG sites in E6/E7 promoter (31, 37, 43, 52, 58) were hypomethylation in cervical cancer group (21.86%, 28.15%, 21.37%, 26.15%, 15.48%, respectively), hypermethylation in asymptomatic group, and middle-methylation in CIN group, in which there were significant difference among three groups (all P < 0.01). The CpG site in 7032, 7091, 7136 of the 3' region of L1 gene was also different methylated among three groups (all P < 0.01). Hypermethylation was found in cancer group (18.89%, 27.72%), hypomethylation was found in asymptomatic group (2.71%, 6.95%) in 7032 and 7091. In 7136, the highest methylation was detected in CIN (66.45%), the lowest in asymptomatic (34.85%), middle in cancer group (46.43%). CONCLUSION: The methylation status of CpG sites in the 3' region of L1 gene and E6/E7 promoter of HPV16 is significant different among three groups, which is likely to anticipate the pathogenesis of CIN and cervical cancer.

The role of TCGA molecular classification in clear cell endometrial carcinoma.

Clear cell endometrial carcinoma (CCEC) represents a relatively rare and heterogeneous entity. Based on The Cancer Genome Atlas (TCGA) molecular classification, the risk stratification and management of endometrial cancer (EC) have been improved. Although the relationship of CCEC with the TCGA classification is less well understood, data has emerged to suggest that molecular classification plays an important role in the prognosis and management of CCEC. Most of patients with CCEC are characterized by p53abn or NSMP type and the prognosis of these patients is poor, whereas those with MMRd or POLEmut seem to have a favorable prognosis. Adjuvant therapy is recommended in CCEC with p53abn and NSMP. Advanced/recurrent CCEC with MMRd benefit much more from immune checkpoint inhibitors after the failure of platinum-based chemotherapy. In addition, bevacizumab plus chemotherapy upfront seems to improve outcomes of advanced/recurrent patients whose tumors harbored mutated TP53, including CCECs with p53abn. Further studies which exclusively recruit CCEC are urgently needed to better understand the role of molecular classification in CCEC. This review will provide an overview of our current understanding of TCGA classification in CCEC.

Extracellular Vesicles Derived from Mesenchymal Stem Cells as Cell-Free Therapy for Intrauterine Adhesion.

Intrauterine adhesion (IUA) can occur after trauma to the basal layer of the endometrium, contributing to severe complications in females, such as infertility and amenorrhea. To date, the proposed therapeutic strategies are targeted to relieve IUA, such as hysteroscopic adhesiolysis, Foley catheter balloon, and hyaluronic acid injection have been applied in the clinic. However, these approaches showed limited effects in alleviating endometrial fibrosis and thin endometrium. Mesenchymal stem cells (MSCs) can offer the potential for endometrium regeneration owing to reduce inflammation and release growth factors. On this basis, MSCs have been proposed as promising methods to treat intrauterine adhesion. However, due to the drawbacks of cell therapy, the possible therapeutic use of extracellular vesicles released by stem cells is raising increasing interest. The paracrine effect, mediated by MSCs derived extracellular vehicles (MSC-EVs), has recently been suggested as a mechanism for their therapeutic properties. Here, we summarizes the main pathological mechanisms involved in intrauterine adhesion, the biogenesis and characteristics of extracellular vesicles, explaining how these vesicles could provide new opportunities for MSCs.

Prognosis and adjuvant chemotherapy for patients with malignant peritoneal cytology in early-stage non-endometrioid endometrial cancer.

OBJECTIVE: To investigate the influence of malignant peritoneal cytology (MPC) on the prognosis of early-stage patients with endometrial clear cell carcinoma(CCC) and serous carcinoma(SC), and the value of chemotherapy in their treatment. METHODS: A retrospective observational cohort study was conducted by querying the National Cancer Institute's Surveillance, Epidemiology, and End Results Program from 2010 to 2019. Women with early-stage CCC and SC with available peritoneal cytology results were enrolled. Propensity score matching(PSM) and propensity score inverse probability of treatment weighting (IPTW) was used to balance the measured covariates in each sub-cohort. RESULTS: A total of 3,616 eligible patients were included, and 368 patients had MPC (10.2%). Women with MPC were more likely to receive postoperative chemotherapy (OR 2.033; 95%CI 1.589-2.602). In PSM model, MPC had worse overall survival(OS) and cancer-specific survival (CSS) (All,p < 0.001). The 5-year OS rates were 56.5% for women with MPC and 74.4% for those with negative peritoneal cytology, and the 5-year CSS rates were 60.8% versus 80.0%(All, p < 0.0001). In the subgroup analyses, MPC was associated with decreased OS and CSS in serous, clear cell histology group, and stage IA cases(All,p < 0.001), but not for stage IB or stage II disease. In multivariate analysis, chemotherapy improved the prognosis of patients with MPC(OS:p = 0.005; CSS:p = 0.010). Additionally, in stage IA subgroup, chemotherapy improved survival outcomes in patients with MPC(OS:P = 0.025; CSS:P = 0.038), in NPC patients, however, chemotherapy was a good prognostic factor for OS (P = 0.001) but not for CSS(P = 0.300). CONCLUSION: MPC was a prognostic factor for decreased survival in early-stage endometrial CCC and SC, and those with MPC could further benefit from chemotherapy.

Immunomodulatory hybrid micro-nanofiber scaffolds enhance vascular regeneration.

The inertness of synthetic polymer materials and the insufficient mechanical strength of reprocessed decellularized extracellular matrix (dECM) limited their promotive efforts on tissue regeneration. Here, we prepared a hybrid scaffold composed of PCL microfibers and human placental extracellular matrix (pECM) nanofibers by co-electrospinning, which was grafted with heparin and further absorbed with IL-4. The hybrid scaffold with improved hemocompatibility firstly switched macrophages to anti-inflammatory phenotype (increased by 18.1%) and then promoted migration, NO production, tube formation of endothelial cells (ECs), and migration and maturation of vascular smooth muscle cells (VSMCs), and ECM deposition in vitro and in vivo. ECs coverage rate increased by 8.6% and the thickness of the smooth muscle layer was 1.8 times more than PCL grafts at 12 wks. Our study realized the complementary advantages of synthetic polymer materials and dECM materials, and opened intriguing perspectives for the design and construction of small-diameter vascular grafts (SDVGs) and immune-regulated materials for other tissue regeneration.

Inhibition of TMUB1 blocks apoptosis and NF-κB pathway-mediated inflammation in recurrent spontaneous abortion.

INTRODUCTION: Approximately 50% of cases with recurrent spontaneous abortion (RSA) have unexplained etiology. Aberrant expression of transmembrane and ubiquitin-like domain containing 1 (TMUB1) is closely related to a series of diseases, including RSA. However, the function and underlying mechanism of TMUB1 in the occurrence of RSA has not been described. METHODS: TMUB1 expression was detected in the placental villous tissues of 30 women with normal miscarriages and 12 women with RSA. The pregnant mice were injected intraperitoneally with lipopolysaccharide (LPS) to induce abortion. Human chorionic trophoblast cells were treated with LPS. Pathological analysis of placental tissues was performed by hematoxylin and eosin staining. RESULTS: TMUB1 was highly expressed in the placental villous tissues of RSA patients compared to the patients who underwent induced abortions. After LPS administration, the mice exhibited high embryo absorption and pathological alterations, as well as presented an increase in inflammation and apoptosis (the etiology of RSA induction) in placental tissues. Moreover, the upregulated expression of TMUB1 was also found in placental tissues of LPS-induced mice, and further investigation showed that TMUB1 deficiency blocked embryo loss as well as inhibited apoptotic rate and inflammation after LPS activation. Furthermore, we found that the loss of TMUB1 suppressed the phosphorylation of IkappaB kinase (IKK) α/ß and attenuated cytoplasmic-nuclear translocation of nuclear factor-κB (NF-κB) p65 in LPS-induced cells. CONCLUSION: Our results indicate that TMUB1 may involve in the modulation of apoptosis and NF-κB pathway-mediated inflammation in RSA. Therefore, TMUB1 may develop as a potential biomarker for RSA treatment.

PDIA4 confers resistance to ferroptosis via induction of ATF4/SLC7A11 in renal cell carcinoma.

The prognosis of renal cell carcinoma (RCC) remains poor due to metastases and resistance to chemotherapy. Salinomycin (Sal) exhibits the potential of antitumor, while the underlying mechanism is not completely clear. Here, we found that Sal induced ferroptosis in RCCs and identified Protein Disulfide Isomerase Family A Member 4 (PDIA4) as a mediator of Sal's effect on ferroptosis. Sal suppressed PDIA4 by increasing its autophagic degradation. Downregulation of PDIA4 increased the sensitivity to ferroptosis, while ectopic overexpression of PDIA4 conferred ferroptosis resistance to RCCs. Our data showed that downregulation of PDIA4 suppressed activating transcription factor 4 (ATF4) and its downstream protein SLC7A11 (solute carrier family 7 member 11), thereby aggravating ferroptosis. In vivo, the administration of Sal promoted ferroptosis and suppressed tumor progress in the xenograft mouse model of RCC. Bioinformatical analyses based on clinical tumor samples and database indicated a positive correlation exists between PDIA4 and PERK/ATF4/SLC7A11 signaling pathway, as well as the malignant prognosis of RCCs. Together, our findings reveal that PDIA4 promotes ferroptosis resistance in RCCs. Treatment of Sal sensitizes RCC to ferroptosis via suppressing PDIA4, suggesting the potential therapeutical application in RCCs.

A novel ultrasound probe calibration method for multimodal image guidance of needle placement in cervical cancer brachytherapy.

PURPOSE: Interstitial needles placement is a critical component of combined intracavitary/interstitial (IC/IS) brachytherapy (BT). To ensure precise placement of interstitial needles, we proposed a novel ultrasonic (US) probe calibration method to accurately register the US image in the magnetic resonance imaging (MRI) image and provide multimodal image guidance for needle placement. METHODS: A wire-based calibration phantom combined with the stylus was developed for the calibration of US probe. The calibration phantom helps to quickly align the imaging plane of the US probe with the fiducial points to obtain US images of these points. The coordinates of fiducial points in US images were located automatically by feature extraction algorithms and were further corrected by the proposed correction method. Ingenious structures were designed on both sides of the calibration phantom to accurately obtain the coordinates of the fiducial points relative to the tracking device. Marker validation and pelvic phantom study were performed to evaluate the accuracy of the proposed calibration method. RESULTS: In the marker validation, the US probe calibration method with corrected transformation achieves a registration accuracy of 0.694 ± 0.014 mm, and the uncorrected one is 0.746 ± 0.018 mm. In the pelvic phantom study, the needle tip difference was 1.096 ± 0.225 mm and trajectory difference was 1.416 ± 0.284 degrees. CONCLUSION: The proposed US probe calibration method is helpful to achieve more accurate multimodality image guidance for needle placement.

Clinical outcome of FIGO 2018 stage IB3/IIA2 cervical cancer treated by neoadjuvant chemotherapy followed by radical surgery due to lack of radiotherapy equipment: A retrospective comparison with concurrent chemoradiotherapy.

This study aimed to assess neoadjuvant chemotherapy's clinical outcomes such as efficacy, toxicity, and survival outcomes followed by radical hysterectomy ((NACT-RS) among women with cervical cancer stage IB3 and IIA2, by comparing concurrent chemoradiotherapy (CCRT) and NACT-RS. The study retrospectively reviewed patients with (2018 FIGO) stage IB3 and IIA2 cervical cancer who received preoperative neoadjuvant chemotherapy followed by NACT-RS or concurrent chemoradiotherapy (CCRT). The outcome measures were the 5-year survival and complication rates between the two groups. The median follow-up was 75 months. In total, 218 patients had stage IIA2, 136 patients had stage IB3, 201 patients received CCRT, and 153 patients received preoperative NACT-RS. In the CCRT group, the incidence of early complications (myelosuppression, gastrointestinal and urinary) was higher compared with that in the NACT-RS group (76.1 vs. 26.1%; p < 0.001, respectively). There was no significant difference between the two study groups concerning late complications. Five-year PFS was 79.9% and 85.5% in the NACT-RS and CCRT groups, respectively (p = 0.093). Five-year OS was 86.9% and 85.5% in the NACT-RS and CCRT groups, respectively (p = 0.97). In the multivariate clinicopathologic characteristics analysis for OS, initial tumor size > 4.3 cm (HR 5.11; p < 0.001), AC/ASC (HR 1.89; p = 0.02), histologic grade 2-3 (HR 2.25; p = 0.04), and 2018 FIGO stage IIA2 (HR 8.67; p < 0.001) were independent risk factors. The survival of patients with stage IB3 and IIA2 cervical cancer treated with NACT-RS was similar to that of patients treated with CCRT without increasing side effects.

Deep reinforcement learning for treatment planning in high-dose-rate cervical brachytherapy.

PURPOSE: High-dose-rate (HDR) brachytherapy (BT) is an effective cancer treatment method in which the radiation source is placed within the body. Treatment planning is a critical component for a successful outcome. Almost all currently proposed treatment planning methods are built on stochastic heuristic algorithms, which limits the generation of higher quality plans. This study proposed a novel treatment planning method to adjust dwell times in a human-like fashion to improve the quality of the plan. METHODS: We built an intelligent treatment planner network (ITPN) based on deep reinforcement learning (DRL). The network architecture of ITPN is Dueling Double-Deep Q Network. The state is the dwell time of each dwell position and the action is which dwell time to adjust and how to adjust it. A hybrid equivalent uniform dose objective function was established and assigned corresponding rewards according to its changes. Experience replay was performed with the epsilon greedy algorithm and SumTree data structure. RESULTS: In the evaluation of ITPN using 20 patient cases, D90, D100 and V100 showed no significant difference compared with inverse planning simulated annealing (IPSA) optimization. However, D2cc of bladder, rectum and sigmoid, V150 and V200 were significant reduced, and homogeneity index and conformity index were significantly increased. CONCLUSION: The proposed ITPN was able to generate higher quality plans based on the learned dwell time adjustment policy than IPSA. This is the first artificial intelligence system that can directly determine the dwell times of HDR BT, which demonstrated the potential feasibility of solving optimization problems via DRL.