Endometrium-derived mesenchymal stem cells suppress progression of endometrial cancer via the DKK1-Wnt/ß-catenin signaling pathway.

BACKGROUND: Mesenchymal stem cell (MSC) therapy is an attractive treatment option for various cancers. Whether MSCs can be used to treat well-differentiated endometrial cancer (EC) remains unclear. The aim of this study is to explore the potential therapeutic effects of MSCs on EC and the underlying mechanisms. METHODS: The effects of adipose-derived MSCs (AD-MSCs), umbilical-cord-derived MSCs (UC-MSCs), and endometrium-derived MSCs (eMSCs) on the malignant behaviors of EC cells were explored via in vitro and in vivo experiments. Three EC models, including patient-derived EC organoid lines, EC cell lines, and EC xenograft model in female BALB/C nude mice, were used for this study. The effects of MSCs on EC cell proliferation, apoptosis, migration, and the growth of xenograft tumors were evaluated. The potential mechanisms by which eMSCs inhibit EC cell proliferation and stemness were explored by regulating DKK1 expression in eMSCs or Wnt signaling in EC cells. RESULTS: Our results showed that eMSCs had the highest inhibitory effect on EC cell viability, and EC xenograft tumor growth in mice compared to AD-MSCs and UC-MSCs. Conditioned medium (CM) obtained from eMSCs significantly suppressed the sphere-forming ability and stemness-related gene expression of EC cells. In comparison to AD-MSCs and UC-MSCs, eMSCs had the highest level of Dickkopf-related protein 1 (DKK1) secretion. Mechanistically, eMSCs inhibited Wnt/ß-catenin signaling in EC cells via secretion of DKK1, and eMSCs suppressed EC cell viability and stemness through DKK1-Wnt/ß-catenin signaling. Additionally, the combination of eMSCs and medroxyprogesterone acetate (MPA) significantly inhibited the viability of EC organoids and EC cells compared with eMSCs or MPA alone. CONCLUSIONS: The eMSCs, but not AD-MSCs or UC-MSCs, could suppress the malignant behaviors of EC both in vivo and in vitro via inhibiting the Wnt/ß-catenin signaling pathway by secreting DKK1. The combination of eMSCs and MPA effectively inhibited EC growth, indicating that eMSCs may potentially be a new therapeutic strategy for young EC patients desiring for fertility preservation.

Multi-Omic Profiling of Multi-Biosamples Reveals the Role of Amino Acid and Nucleotide Metabolism in Endometrial Cancer.

Background: Endometrial cancer (EC) is one of the most common gynecological cancers. The traditional diagnosis of EC relies on histopathology, which, however, is invasive and may arouse tumor spread. There have been many studies aiming to find the metabolomic biomarkers of EC to improve the early diagnosis of cancer in a non-invasive or minimally invasive way, which can also provide valuable information for understanding the disease. However, most of these studies only analyze a single type of sample by metabolomics, and cannot provide a comprehensive view of the altered metabolism in EC patients. Our study tries to gain a pathway-based view of multiple types of samples for understanding metabolomic disorders in EC by combining metabolomics and proteomics. Methods: Forty-four EC patients and forty-three controls were recruited for the research. We collected endometrial tissue, urine, and intrauterine brushing samples. Untargeted metabolomics and untargeted proteomics were both performed on the endometrial tissue samples, while only untargeted metabolomics was performed on the urine and intrauterine brushing samples. Results: By integrating the differential metabolites and proteins between EC patients and controls detected in the endometrial tissue samples, we identified several EC-related significant pathways, such as amino acid metabolism and nucleotide metabolism. The significance of these pathways and the potential of metabolite biomarker-based diagnosis were then further verified by using urine and intrauterine brushing samples. It was found that the regulation of metabolites involved in the significant pathways showed similar trends in the intrauterine brushings and the endometrial tissue samples, while opposite trends in the urine and the endometrial tissue samples. Conclusions: With multi-omics characterization of multi-biosamples, the metabolomic changes related to EC are illustrated in a pathway-based way. The network of altered metabolites and related proteins provides a comprehensive view of altered metabolism in the endometrial tissue samples. The verification of these critical pathways by using urine and intrauterine brushing samples provides evidence for the possible non-invasive or minimally invasive biopsy for EC diagnosis in the future.

NrCAM secreted by endometrial stromal cells enhances the progestin sensitivity of endometrial cancer cells through epigenetic modulation of PRB.

Progestin is one of the main hormone treatment regimens for early-stage estrogen receptor- and progesterone receptor (PR)-positive endometrial cancer (EC). However, the response rate of EC to progestins is unsatisfactory. Investigating the mechanisms related to progestin treatment could help improve treatment efficacy. Studies have demonstrated that normal endometrial stromal cells (ESCs) increase the inhibitory effect of progestin on EC cell proliferation via paracrine signaling, but the mechanisms involved remain unclear. In this study, we found that ESCs had different morphological features between progestin-sensitive and -insensitive EC tissues. ESCs presented typical decidualization changes in progestin-sensitive cases, while they remained slim in progestin-insensitive EC lesions, indicating no response. Furthermore, ESCs enhanced the inhibitory effect of medroxyprogesterone acetate (MPA) on EC cell proliferation by secreting neuron cell adhesion molecule (NrCAM). MPA treatment enhanced NrCAM secretion by ESCs. EC xenografts in BALB/C nude mice demonstrated that MPA combined with NrCAM had an increased tumor inhibitory effect compared with MPA or NrCAM alone. Mechanistically, MPA upregulated NrCAM expression in ESCs through PR. Specifically, NrCAM increased PR expression in EC cells through TET1-induced hydroxymethylation of the PRB gene promoter region. These findings indicate that NrCAM or NrCAM combined with progestins could be a new EC treatment.

Astragalus polysaccharide (APS) exerts protective effect against acute ischemic stroke (AIS) through enhancing M2 micoglia polarization by regulating adenosine triphosphate (ATP)/ purinergic receptor (P2X7R) axis.

Clinically, the effective treatment for patients with acute ischemic stroke (AIS) is very limited. Therefore, this paper aims to investigate the mechanism how astragalus polysaccharide (APS) exerts protective effect against AIS and provide a new method for the treatment of AIS. Cell surface antigen flow cytometry and immunofluorescence were used to identify M1 and M2 microglia. Western blot was used to evaluate the expression of associated protein. Oxygen-glucose deprivation (OGD) was used to simulate the effect of AIS on rat microglia. The middle cerebral artery occlusion (MCAO) model was established to simulate the effect of AIS in vivo. Evans blue dye (EBD) was used to evaluate the permeability of blood-brain barrier (BBB). Western blot and cell surface antigen flow cytometry results showed that APS promoted the M2 polarization of rat microglia by inhibiting the expression of purinergic receptor (P2X7R). APS reversed the effect of OGD on the polarization of rat microglia M1/ M2 by regulating P2X7R. APS reversed the effect of MCAO on the polarization of rat microglia M1/ M2 in vivo. Furthermore, APS inhibited the expression of P2X7R by promoting the degradation of adenosine triphosphate (ATP) in the cerebral cortex of MCAO rats. In addition, APS contributed to maintain the integrity of BBB. Summarily, APS can reduce brain injury by promoting the degradation of ATP in microglia and inhibiting the expression of P2X7R after AIS.

Diagnostic value of Lipoarabinomannan antigen for detecting Mycobacterium tuberculosis in adults and children with or without HIV infection.

OBJECTIVES: Even today, tuberculosis (TB) remains a leading public health problem; yet, the current diagnostic methods still have a few shortcomings. Lipoarabinomannan (LAM) provides an opportunity for TB diagnosis, and urine LAM detection seems to have a promising and widely applicable prospect. DESIGN OR METHODS: Four databases were systematically searched for eligible studies, and the quality of the studies was evaluated using the quality assessment of diagnostic accuracy studies-2 (QUADAS-2). Graphs and tables were created to show sensitivity, specificity, likelihood ratios, diagnostic odds ratio (DOR), the area under the curve (AUC), and so on. RESULTS: Based on the included 67 studies, the pooled sensitivity of urine LAM was 48% and specificity was 89%. In the subgroup analyses, the FujiLAM test had higher sensitivity (69%) and specificity (92%). Furthermore, among patients infected with human immunodeficiency virus (HIV), 50% of TB patients were diagnosed using a urine LAM test. Besides, the CD4+ cell count was inversely proportional to the sensitivity. CONCLUSIONS: Urine LAM is a promising diagnostic test for TB, particularly using the FujiLAM in HIV-infected adults whose CD4+ cell count is ≤100 per µl. Besides, the urine LAM test shows various sensitivities and specificities in different subgroups in terms of age, HIV infection status, CD4+ cell count, and testing method.

Retraction notice to "Residual papaya promoting the growth performance, antioxidant, nonspecific immunity of juvenile Tilapia mossambica" [Fish Shellfish Immunol. 98 (2020) 605-610].

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of Editors-in-Chief and first Author. The article duplicates significant parts of a paper that had already appeared in Fish & Shellfish Immunology, Volume 93 (2019) 726-731, https://doi.org/10.1016/j.fsi.2019.06.052. One of the conditions of submission of a paper for publication is that authors declare explicitly that the paper has not been previously published and is not under consideration for publication elsewhere. As such this article represents a misuse of the scientific publishing system. The scientific community takes a very strong view on this matter and apologies are offered to readers of the journal that this was not detected during the submission process. The article was published without the knowledge of the co-authors.

RETRACTED: Residual papaya promoting the growth performance, antioxidant, nonspecific immunity of juvenile Tilapia mossambica.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of Editors-in-Chief and first Author. The article duplicates significant parts of a paper that had already appeared in Fish & Shellfish Immunology, Volume 93 (2019) 726-731, https://doi.org/10.1016/j.fsi.2019.06.052. One of the conditions of submission of a paper for publication is that authors declare explicitly that the paper has not been previously published and is not under consideration for publication elsewhere. As such this article represents a misuse of the scientific publishing system. The scientific community takes a very strong view on this matter and apologies are offered to readers of the journal that this was not detected during the submission process. The article was published without the knowledge of the co-authors.

The biodegradation of carbaryl in soil with Rhodopseudomonas capsulata in wastewater treatment effluent.

In this study, the effects of Rhodopseudomonas capsulata present in wastewater effluent on the biodegradation of carbaryl in soil and improvement of soil fertility were investigated. Compared to control treatment, carbaryl was removed efficiently and soil fertility was remediated with the addition of effluent containing R. capsulata. Molecular analysis revealed that carbaryl induced carbaryl hydrolase gene expression to synthesize carbaryl hydrolase through activating MAPKKKs, MAPKKs, MAPKs genes in MAPK signal transduction pathway. The induction and secretion of carbaryl hydrolase occur after one day in R. capsulata, which can be attributed to its characteristics as an ancient bacteria, which require acclimatization to carbaryl before gene induction. However, lack of organics in soil and control treatment could not maintain R. capsulata growth for over one day. The residual organics in the effluent provided sufficient carbon source and energy for R. capsulata under four effluent treatments. This new method resulted in the remediation of carbaryl pollution and improvement of soil fertility and soybean processing wastewater treatment simultaneously, as well as the reutilization of wastewater and R. capsulata as sludge. Meanwhile, the high-order non-linear mathematical model about carbaryl removal rate was established.

Treatment efficiency of comprehensive hysteroscopic evaluation and lesion resection combined with progestin therapy in young women with endometrial atypical hyperplasia and endometrial cancer.

OBJECTIVE: This study aimed to evaluate the efficacy of comprehensive hysteroscopic evaluation and lesion resection combined with progestin therapy in young patients with endometrial atypical hyperplasia (EAH) and early stage endometrial cancer (EEC) who wished to preserve their fertility. METHODS: Patients with EAH (n = 120) or well-differentiated EEC (n = 40, FIGO stage IA, without myometrial invasion) were retrospectively included. All patients received constant oral progestin combined with hysteroscopic evaluation every 3 months until achieving complete response (CR). The location, number and size of each suspected lesion or cluster were detailly recorded during the hysteroscopy. RESULTS: The median age was 32.0 year-old (range, 22-47 year-old). Totally 148 patients (97.4%) achieved CR while 3 EAH and 1 EEC patients presented with disease progression, and 8 patients were still in treatment. The mean treatment duration for achieving CR was 6.7 ±â€¯0.3 months (range, 1-18 months). After adjusting for patient age, body mass index (BMI), history of pregnancy and type of conservative therapies, lesion size ≤2 cm (OR, 0.701; 95% CI, 0.496-0.991; P = 0.045) was significantly correlated with shorter treatment time to achieve CR. Among 60 patients attempted to conceive after achieving CR, 45.0% (15/60) had been pregnant, 25.0% (15/60) delivered live birth, 13.3% (8/60) are still in pregnancy, while 6.7% experienced spontaneous abortion. CONCLUSION: Comprehensive hysteroscopic evaluation and lesion resection plus progestin therapy seem to be an effective and safe fertility sparing therapy for patients with EAH or EEC. Endometrial lesion size ≤2 cm correlated with a shorter treatment period to achieve CR.

The prognostic significance of estrogen and progesterone receptors in grade I and II endometrioid endometrial adenocarcinoma: hormone receptors in risk stratification.

OBJECTIVES: Although patients with grade I and II endometrioid endometrial adenocarcinoma (EEA) are considered with good prognosis, among them 15%-25% died in 5 years. It is still unknown whether integrating estrogen receptor (ER) and progesterone receptor (PR) into clinical risk stratification can help select high-risk patients with grade I-II EEA. This study was to investigate the prognostic value of ER and PR double negativity (ER/PR loss) in grade I-II EEA, and the association between ER/PR loss and The Cancer Genome Atlas (TCGA) classification. METHODS: ER and PR were assessed by immunohistochemistry on hysterectomy specimens of 903 patients with grade I-II EEA. ER and PR negativity were determined when <1% tumor nuclei were stained. Gene expression data were obtained from the TCGA research network. RESULTS: Compared with ER or PR positive patients (n=868), patients with ER/PR loss (n=35) had deeper myometrial infiltration (p=0.012), severer FIGO stage (p=0.004), and higher rate of pelvic lymph node metastasis (p=0.020). In univariate analysis, ER/PR loss correlated with a shorter progression-free survival (PFS; hazard ratio [HR]=5.25; 95% confidence interval [CI]=2.21-12.52) and overall survival (OS; HR=7.59; 95% CI=2.55-22.60). In multivariate analysis, ER/PR loss independently predicted poor PFS (HR=3.77; 95% CI=1.60-10.14) and OS (HR=5.56; 95% CI=1.37-22.55) for all patients, and poor PFS for patients in stage IA (n=695; HR=5.54; 95% CI=1.28-23.89) and stage II-IV (n=129; HR=5.77; 95% CI=1.57-21.27). No association was found between ER/PR loss and TCGA classification. CONCLUSION: Integrating ER/PR evaluation into clinical risk stratification may improve prognosis for grade I-II EEA patients.

A20-mediated deubiquitination of ERα in the microenvironment of CD163+ macrophages sensitizes endometrial cancer cells to estrogen.

Continuous estrogen signaling is thought to be the main mechanism causing endometrial cancer (EC). Studies have demonstrated that CD163+ macrophages could promote the development of estrogen-dependent EC, but the mechanisms involved remain unclear. We found that CD163+ macrophages were the dominant macrophages in atypical endometrial hyperplasia and cancer, and their infiltration was positively associated with ERα expression. CD163+ macrophages mainly increased ERα protein levels but with little upregulatory effect on ESR1 (ERα coding gene) transcripts. The ubiquitin-editing enzyme A20, screened from the endometrial microarray obtained from mice receiving a high-fat diet and sustained estrogen-intervened, was highly expressed in endometrial lesions rich with CD163+ macrophages, and positively correlated with ERα expression. Similarly, A20 and ERα were both upregulated by CD163+ macrophages via cytokines such as IL1α, IL17A and TNFα. Mechanistically, A20 overexpression in EC cells prolonged ERα protein half-life without affecting ESR1 transcripts. A20 increased functional ERα protein levels and enhanced estrogen-driven EC cell proliferation through preventing ERα protein degradation by its deubiquitinase activity. Our study revealed that A20-mediated deubiquitination of ERα might be an important mechanism by which CD163+ macrophages sensitize EC cells to estrogen.

Five cases of uterine perivascular epithelioid cell tumors (PEComas) and review of literature.

OBJECTIVES: Perivascular epithelioid cell tumor (PEComa) is a rare condition and the recognition of this condition is limited. Here we report five cases of uterine PEComa to add to the limited understanding of this rare condition. METHODS: Five cases from Obstetrics and Gynecology Hospital of Fudan University were diagnosed as uterine PEComas. We collected the patients' clinical and pathological data as well as their outcomes. RESULTS: All the five cases were diagnosed post-operationally. Fertility-sparing surgery was done for the first case and had a mass resection only. She delivered a healthy boy through the cesarean section in November 2016 and neither recurrence nor metastasis was found for 71 months. Hysterectomy was done for the other four cases. Adjuvant chemotherapy was also given for case 2 and case 4. Case 2 had combined endometrial cancer, which could be associated with tuberous sclerosis complex (TSC). She was followed up for 22 months and neither recurrence nor metastasis was detected. Neither recurrence nor metastasis was found in case 3 for 33 months. However, the patient in case 4 died of multiple dissemination and multiple organs failures, 10 months after the second surgery. The patient in case 5 had the hysterectomy and left adnexal resection and in this case we had no data about her long-term outcomes. CONCLUSION: It is still challenging to detect and diagnose uterine PEComa clinically and no consensus or guidelines have been established regarding the treatment of this condition. More case studies are needed to enlighten the underlying mechanism and help optimize the therapies for this condition.

Insulin resistance and overweight prolonged fertility-sparing treatment duration in endometrial atypical hyperplasia patients.

OBJECTIVE: Our previous study showed that insulin resistance (IR) was related to endometrial hyperplasia as well as endometrial cancer. But the exact impact of IR on fertility-sparing treatment in endometrial hyperplasic disease is unclear. This study investigated how IR affects fertility-sparing treatment in endometrial atypical hyperplasia (EAH) patients. METHODS: The 151 EAH patients received fertility-sparing treatment were retrospectively investigated. All patients received high-dose progestin combined with hysteroscopy. Therapeutic effects were evaluated by hysteroscopy every 3 months during the treatment. RESULTS: The median age was 33.0 years old (range, 21-54 years old). Sixty-one patients (40.4%) were insulin resistant. Three patients were excluded from the analysis because they chose hysterectomy within 3 months after initiation of progestin treatment. The 141 out of 148 (95.3%) patients achieved complete response (CR). No difference was found in cumulative CR rate between those with or without IR (90.2% vs. 95.6%, p=0.320). IR significantly affected therapeutic duration to achieve CR (8.1±0.5 months with IR vs. 6.1±0.4 months without IR, p=0.004). Overweight (body mass index [BMI]≥25 kg/m²) was associated with higher risk of treatment failure (odds ratio=5.61; 95% confidence interval=1.11-28.35; p=0.040) and longer therapeutic duration to achieve CR (7.6±0.5 months vs. 6.3±0.4 months, p=0.019). EAH patients with both IR and overweight (IR+BMI+) had the longest therapeutic time compared with other patients (8.8±0.6 months vs. 5.6±0.7, 6.3±0.4, and 6.4±0.8 months for IR-BMI+, IR-BMI-, and IR+BMI-, respectively, p=0.006). CONCLUSION: IR and overweight were associated with longer therapeutic duration in EAH patients receiving progestin-based fertility-sparing treatment.

Estrogen and high-fat diet induced alterations in C57BL/6 mice endometrial transcriptome profile.

Unopposed estrogen stimulation and insulin resistance are known to play important roles in endometrial cancer (EC), but the interaction between these two factors and how they contribute to endometrial lesions are not completely elucidated. To investigate the endometrial transcriptome profile and the associated molecular pathway alterations, we established an ovariectomized C57BL/6 mouse model treated with subcutaneous implantation of 17-ß estradiol (E2) pellet and/or high-fat diet (HFD) for 12 weeks to mimic sustained estrogen stimulation and insulin resistance. Histomorphologically, we found that both E2 and E2 + HFD groups showed markedly enlarged uterus and increased number of endometrial glands. The endometrium samples were collected for microarray assay. GO and KEGG analysis showed that genes regulated by E2 and/or HFD are mainly responsible for immune response, inflammatory response and metabolic pathways. Further IPA analysis demonstrated that the acute phase response signaling, NF-κB signaling, leukocyte extravasation signaling, PPAR signaling and LXR/RXR activation pathways are mainly involved in the pathways above. In addition, the genes modulated reciprocally by E2 and/or HFD were also analyzed, and their crosstalk mainly focuses on enhancing one another's activity. The combination analysis of microarray data and TCGA database provided potential diagnostic or therapeutic targets for EC. Further validation was performed in mice endometrium and human EC cell lines. In conclusion, this study unraveled the endometrial transcriptome profile alterations affected by E2 and/or HFD that may disturb endometrial homeostasis and contribute to the development of endometrial hyperplasia.

Advances in antitumor functions and mechanisms of apolipoprotein A-Ⅰ / 中国肿瘤临床

Apolipoprotein A-Ⅰ (ApoA-Ⅰ), the predominant protein in plasma HDL, regulates cholesterol metabolism and exhibits anti-in-flammatory and antioxidant functions. Multiple clinical studies suggest that serum ApoA-Ⅰ levels are associated with the occurrence, development, and prognosis of malignant tumors. Laboratory research also shows that ApoA-Ⅰ and ApoA-Ⅰ mimetics exert antitumor ef-fects through antioxidation, immunoregulation, cholesterol metabolism, lysophosphatidic acid binding, and anti-angiogenesis. This pa-per reviews the role of ApoA-Ⅰ and ApoA-Ⅰ peptides in tumorigenesis and their potential value in diagnosis, treatment, and prognosis.

Determination of complementary antibody pairs using protein A capture with the AlphaScreen assay format.

The utility of antibody reagents for the detection of specific cellular targets for both research and diagnostic applications is widespread and continually expanding. Often it is useful to develop specific antibodies as reagent pairs that distinguish different epitopes of the target such that sandwich enzyme-linked immunosorbent assay can be used for selective and specific detection. However, the identification of pairing antibodies is often cumbersome and labor-intensive even with the use of designed peptide-specific epitopes as antigens. We have developed a robust and high-throughput method for identifying pairing complementary antibodies derived either from commercial sources or during a rabbit hybridoma monoclonal screening and selection process using protein A capture with the AlphaScreen bead-based assay format. We demonstrate the value and effectiveness of this assay with three protein targets: Akt2, ATF3, and NAEß (the ß-subunit of the neddylation activation enzyme).

[The hardware design of a portable gastrointestinal wireless endoscope image receiver].

The portable gastrointestinal wireless endoscope image receiver is developed and based on TMS320C6211 DSP. It can receive and demodulate the modulated signal which is transmitted from the camera-capsule, and then output the video signal. The synchronizing signals offered by SAA7114H are made best of and are used to design the time logic circuit. The fitful video signal can be collected under the control of the time logic circuit. The circuit can automatically get rid of useless blank data and only collect effective and good-quality video signals, and storage them in CF card. In addition, the image signal can be processed and compressed by DSP, and thus the data storage space and the data- analyzing time can be saved.