Abstract Preeclampsia (PE), a common disorder of pregnancy, is characterized by insufficient trophoblast migration and inadequate vascular remodelling, such that promotion of trophoblast proliferation might ameliorate PE. In the current study, we sought to study the underlying mechanism of extracellular vesicle (EV)‐derived microRNA‐18 (miR‐18b) in PE. Human umbilical cord mesenchymal stem cells (HUCMSCs) isolated from placental tissues were verified through osteogenic, adipogenic and chondrogenic differentiation assays. Bioinformatics analyses and dual‐luciferase reporter gene assay were adopted to confirm the targeting relationship between miR‐18b and Notch2. The functional roles of EV‐derived miR‐18b and Notch2 in trophoblasts were determined using loss‐ and gain‐of‐function experiments, and trophoblast proliferation and migration were assayed using CCK‐8 and Transwell tests. In vivo experiments were conducted to determine the effect of EV‐derived miR‐18b, Notch2 and TIM3/mTORC1 in a rat model of PE, with monitoring of blood pressure and urine proteinuria. TUNEL staining was conducted to observe the cell apoptosis of placental tissues of PE rats. We found down‐regulated miR‐18b expression, and elevated Notch2, TIM3 and mTORC1 levels in the placental tissues of PE patients compared with normal placenta. miR‐18b was delivered to trophoblasts and targeted Notch2 and negatively its expression, whereas Notch2 positively mediated the expression of TIM3/mTORC1. EV‐derived miR‐18b or Notch2 down‐regulation enhanced trophoblast proliferation and migration in vitro and decreased blood pressure and 24 hours urinary protein in PE rats by deactivating the TIM3/mTORC1 axis in vivo. In summary, EV‐derived miR‐18b promoted trophoblast proliferation and migration via down‐regulation of Notch2‐dependent TIM3/mTORC1.
Background: Overt thyroid diseases have been identified as risk factors for female infertility. However, it remains largely unclear whether subclinical hypothyroidism (SCH), a very common thyroid disorder, is associated with female infertility. This study aimed to investigate the potential association between SCH and the ovarian reserve in women seeking infertility treatment. Methods: This retrospective study included 2568 women with normal thyroid function (n = 2279) or SCH (n = 289) who visited our clinic for infertility treatment. Ovarian reserve markers, including follicle-stimulating hormone (FSH) concentrations on days 2-4, the antral follicle count (AFC), and anti-Müllerian hormone (AMH) concentration, were compared between euthyroid women and those with SCH. Multiple linear and Poisson regression analyses were used to estimate the associations of SCH with ovarian reserve markers. These analyses were repeated separately in women aged <35 (n = 1349) and ≥35 years (n = 1219). Results: In the total study population, women with SCH had significantly lower AMH concentrations (median: 2.05 vs. 2.51 ng/mL, p = 0.015) and AFCs (median: 10.0 vs. 11.0, p = 0.013), compared with euthyroid women. In linear and Poisson regression analyses, SCH was significantly associated with a higher basal FSH concentration (mean difference = 1.13 mIU/mL [95% confidence interval (CI) 0.97 to 1.29 mIU/mL], p < 0.001), lower AMH concentration (mean difference = -0.27 ng/mL [CI -0.43 to -0.12 ng/mL], p = 0.001), and lower AFC (mean difference = -0.7 [CI -1.3 to -0.2], p = 0.005). In women aged ≥35 years, SCH was significantly associated with FSH (mean difference = 1.74 mIU/mL, p < 0.001) and AMH concentrations (mean difference = -0.40 mg/mL, p < 0.001) and AFC (mean difference = -0.8, p < 0.001). In women <35 years old, SCH was significantly associated with a higher FSH concentration (mean difference = 0.30 mIU/mL, p < 0.001), but not with AMH or AFC concentrations (p = 0.84 and 0.06, respectively). Thyroperoxidase antibody (TPOAb) positivity was not associated with measures of ovarian reserve. Conclusions: The data suggest that SCH is associated with decreased ovarian reserve during later reproductive age. TPOAb positivity was not associated with ovarian reserve. Future research is necessary to investigate the underlying molecular mechanisms regulating the diminished ovarian reserve in women with SCH and to evaluate whether levothyroxine supplementation may improve the ovarian function of women with SCH.
Abstract Introduction: Chimeric antigen receptor T cells (CAR-T) targeting CD19 have shown great potential for treatment of B-cell malignancies. For those patients who can not achieve complete remission (CR) or suffer from relapse after CAR-T therapy, further therapeutic strategies still remain elusive. Whether existing CAR-T cells can revitalize in vivo and eradicate tumor cells is still unknown. Patient concerns: We report a case of diffused large B-cell lymphoma patient who had achieved CR after CD19 targeted CAR-T therapy but relapsed after 5 months. Diagnosis: Five months after CAR-T cell infusion, the patient was confirmed a relapse by follow-up PET/CT scan and a mass biopsy. Flow cytometry showed a dramatically decreased percentage of CAR-T cells in peripheral blood (PB). Interventions: A second anti-CD19 CAR-T therapy was planned with deliberation. Firstly, the patient received lymphodepletion chemotherapy with fludarabine (25 mg/m 2 , d1–d3) and cyclophosphamide (500 mg/m 2 d2–d3). Outcomes: After fludarabine and cyclophosphamide (FC) lymphodepletion chemotherapy, pre-existing CAR-T cells were revitalized and the patient developed grade 2 cytokine release syndrome (CRS) contributing to the regression of relapsed B-cell lymphoma. Conclusions: This case suggested that FC chemotherapy could revitalize CAR-T cells contributing to the regression of relapsed B-cell lymphoma. Nevertheless, further researches are required in the future as this report described only a single case.
Eupatilin (5,7‐dihydroxy‐3′,4′,6‐trimethoxyflavone) is a natural active substance found in génépi group plants, and its pharmacological activities has been proven to be useful in the treatment of various cancers. However, whether eupatilin demonstrates anti‐cancer activity in cervical cancer is still under evaluation. To clarify this, cancer cell lines and nude mouse model were used in this study. The results indicated that eupatilin could inhibit the occurrence of cervical cancer both in vivo and in vitro. Cervical cancer cell lines (C4‐1, HeLa, Caski, and Siha) and Ect1/E6E7 cells were incubated with eupatilin (40μM) for 48 hours. Compared with the control group, the viability of cervical cancer cells decreased significantly, while the apoptotic cells increased significantly. Cell cycle analysis showed that eupatilin treatment of HeLa and Caski cells reduced the proliferation index. Eupatilin at 40 mg/kg also inhibited tumour growth in tumour‐bearing mice. Interestingly, weakened hedgehog signalling was observed in cervical cancer cells and tumours from tumour‐bearing mice after eupatilin treatment. Our results reveal the inhibitory effect of eupatilin on cervical cancer and shed new light on the molecular mechanism of its therapeutic effect. Significance of the study Eupatilin inhibited proliferation via promoting apoptosis and cell cycle arrest in HeLa and Caski cervical cancer cell lines. In addition, nude mouse tumourigenicity assay proved that eupatilin can suppress tumour growth in vivo. Dramatically, these activities might be involved in hedgehog signal pathway.
e19028 Background: The chimeric antigen receptor (CAR) T cell treatment has been demonstrated as an effective therapy to relapse/refractory B cell malignancy. However, tumor microenvironment influences and affects CAR T treatment. For example, programmed death ligand 1/2 (PDL1/2) may inhibit the CAR T cells via interaction with up-regulated Programmed cell death protein 1 (PD1) during T cells activation, suppressing the tumor-killing capability of the CAR T cells. Thus, blockade of the PD1-PDL1/2 interaction may enhance the anti-tumor efficacy of CAR T therapy. Methods: We generated CAR T cells including an anti-CD19 second generation (2G) CAR molecule and a dominant negative PD1 molecule (Figure A). Compared with conventional CART cells, these “armored” CART cells show the enhanced capability of tumor killing after multiple-round tumor challenging and more “memory-like” phenotypes (Figure B). These results suggest dominant negative PD1 molecules may protect CART cells from exhaustion in the tumor microenvironment. Results: We report clinical trials of three refractory diffuse large B cell lymphomas (DLBCLs) patients that were successfully treated using the armored CAR T cells described above. All of these three patients failed to achieve response after multiple rounds of chemotherapy and radiotherapy. However, after infused with autologous CART cells at 5.23×10^6/kg and 1.97×10^6/kg, respectively, they showed significant tumor mass decrease and SUV max declines in PET/CT results and ongoing responses (e.g., from 34.48 to 3.89 at day 27, from 25.02 to 2.38 at day 31, respectively, see Figure C). Conclusions: These three clinical trials revealed the significant anti-bulky lymphoma response with respect to these armored CAR T cells and limited and tolerated cytokine release syndrome and central nervous system toxicity. Also, dominant negative PD1 molecules may augment CAR T cells persistence in patients after activation by lymphoma cells, thus enhancing the efficacy of CAR T cells in the treatment of hematomas. Finally, the techniques described herein are a platform technology and may be applied to other adoptive cellular immunotherapies such as TCR-T or TIL in the treatment of solid tumors. We are continuing to recruit more patients for the clinical trials. Clinical trial information: ChiCTR1900021295.
e18512 Background: Patients with relapsed/refractory B-ALL are difficult to be treated. Autologous CD19 CAR-T may overcome many limitations of conventional therapies and induce remission in patients with relapsed/refractory disease. We explored treatment of 11 pediatric cases (come from Multicenter) with r/r B-ALL and assessed the clinical safety and efficacy. Methods: We infused autologous CD19 CAR-T in patients at doses of 0.45 × 10 6 to 10.51 × 10 6 cells per kilogram of body weight. Between Oct. 23 2015 and Jan. 12 2017, a total of 11 children from 3 clinical centers (in China) cases were treated with CAR-T cells (Table1). Patients were monitored for a response, toxic effects, and remission rate. Statistical analysis involving categorical or continuous covariates, univariates, or multivariates analyses. Results: 73% (8/11) of the patients achieved complete remission (CR) and MRD negative between Day7-14 after CD19 CART cell infusion. 4 patients received a repeat infusions following initial ones since they have endured the Cytokine release syndrome (CRS) and have no safety concerns. Cytokine release syndrome (CRS) was seen in 73% (8/11) of patients and severe CRS occurred in 18% (2/11) of patients. Severe CRS was relieved gradually when the anti-IL6R agent tocilizumab and Methylprednisolone were administrated. 1 patients performed bone marrow transplant after they achieved MRD negative. The median CR maintenance is 121 day. Conclusions: This effort provides the first large set of pediatrics data that describes the potential for CART19 therapy to benefit Chinese population. Autologous CD19 CAR-T was effective in treating relapsed/refractory B-ALL not only low leukemia burden, but also high-burden leukemia patients. The method also can associated with a high remission rate. Importantly, While the multicenter trial involves 3 clinical centers in China, the variable clinical settings do not seem to impact patient outcomes due to the highly standardized CAR T cell preparation protocol and manageable CRS in most. (NCT 02813837) Clinical trial information: NCT 02813837.
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