Dual-specificity phosphatase 6 predicts the sensitivity of progestin therapy for atypical endometrial hyperplasia.

OBJECTIVE: We previously found that Dual-specificity phosphatase 6 (Dusp6) over-expression enhanced the growth-promoting effect of estrogen in endometrial adenocarcinoma cells. The aim of this study was to explore the correlation of Dusp6 expression with progestin sensitivity in atypical endometrial hyperplasia (AEH) and earlier endometrial carcinomas (EC). METHODS: Using immunohistochemistry study, we analyzed the expression of Dusp6 protein in AEH. RESULTS: We found that progestin treatment was effective in 89% of AEH and 50% of EC. Before treatment, Dusp6 expression was significantly higher in progestin-sensitive AEH groups compared with progestin-resistant groups. After treatment, Dusp6 expression was significantly upregulated in progestin-sensitive groups, but not in progestin-resistant groups. Moreover, a high-dose of Dusp6 transfection significantly enhanced progestin-induced growth-inhibition in Ishikawa cells. CONCLUSIONS: Dusp6 could be a predicting marker for deciding the effectiveness of progestin therapy in AEH.

Loss of expressions of Dusp6, Sprouty4, and Sef, negative regulators of FGF2/ERK1/2 signaling, in the endometrium of women with adenomyosis.

Dual-specificity phosphatase 6 (Dusp6), Sprouty4, and similar expression to FGF (Sef) are negative modulators of FGF2/ERK1/2 signaling. The objective of the study was to evaluate the expressions of Dusp6, Sprouty4, and Sef in eutopic endometria of patients with adenomyosis. Endometria from 30 women with adenomyosis and 29 women without adenomyosis were used in this study. The expressions of Dusp6, Sprouty4, and Sef were investigated by immunohistochemical analysis. We found that Dusp6, Sprouty4, and Sef expressions were present in endometrial epithelial cells of normal endometria and eutopic endometria of adenomyosis. Weak immunostainings were noted in stromal cells in both endometria. No cyclical change was noted either in normal endometria or in eutopic endometria of adenomyosis during menstrual cycle. By immunohistochemical analysis, we found that eutopic endometria of adenomyosis showed significantly decreased Dusp6, Sprouty4, and Sef expressions compared with normal endometria. By in situ hybridization analysis, we found that the mRNA expressions of Dusp6, Sprouty4, and Sef were downregulated in eutopic endometria of adenomyosis compared with normal endometria. We conclude that downregulation of Dusp6, Sprouty4, and Sef--negative modulators of FGF2/ERK1/2 signaling--was present in eutopic endometria of adenomyosis, which may play critical roles in the development of adenomyosis.

Modulation of the Structural, Magnetic, and Dielectric Properties of YMnO3 by Cu Doping.

The lower valence compensation of YMn1-xCuxO3 (x = 0.00, 0.05, and 0.10) is prepared by the solid-state reaction, and the effects of divalent cation Cu-doping on the construction and magnetic and dielectric attributes of multiferroic YMnO3 are systemically researched. Powder X-ray diffraction shows YMn1-xCuxO3 has a single-phase hexagonal construction with a P63cm space group as the parent YMnO3, and lattice parameters decrease systematically as Cu concentration increases. Using the scanning electric microscope, structure morphologies analysis shows that the mean grain size varies between 1.90 and 2.20 µm as Cu content increases. YMn1-xCuxO3 magnetization increases as Cu doping concentration increases, and the antiferromagnetic transition temperature declines from 71 K for x = 0.00 to 58 K for x = 0.10. The valence distributions of Mn ions conduce to the modified magnetic attributes. Due to Cu substitution, the dielectric loss and dielectric constant decline as frequency increases from 400 to 700 K, showing representative relaxation behaviors. Indeed, that is a thermally activated process. In addition, the peak of the dielectric loss complies with the Arrhenius law. The relaxation correlates to the dipole effect regarding carrier hopping between Mn3+ and Mn4+, and also correlates to oxygen vacancies generated by Mn2+.

Relationship Between Occupational Noise Exposure and Gestational Hypertension in Pregnant Women in Taizhou City: Cross-Sectional Study.

OBJECTIVE: In view of the hazards of occupational noise exposure, this study investigated the relationship between occupational noise exposure and gestational hypertension in Taizhou City, Zhejiang Province, China to provide inspiration and reference for reducing the occurrence of gestational hypertension. METHODS: This cross-sectional study analyzed the clinical data of 316 pregnant women in Taizhou City admitted to Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University from May 2020 to May 2023. In accordance with Acoustic Environment Quality Standards (GB3096-2008), 60 dB was used as the cut-off point. These pregnant women were divided into the low noise group (LNG, n = 161) and high noise group (HNG, n = 155) according to the noise exposure level in the working environment. This also study compared the noise exposure, blood pressure (BP), fasting blood glucose (FBG), blood lipid (BL), fetal size, and heart rate (HR), and analyzed the relationship of noise exposure with BP, FBG, BL, fetal size, HR, and occurrence of gestational hypertension. RESULTS: The HNG had higher noise exposure level (P < 0.001), BP, FBG, BL and HR (P < 0.001), larger fetal size (P < 0.001) and higher occurrence of gestational hypertension (P < 0.05) compared with the LNG. Correlation analysis showed that noise exposure level was positively correlated with BP, FBG, BL, HR, and fetal size (P < 0.001) and had the strongest association with gestational hypertension. CONCLUSION: Occupational noise exposure has adverse effects on pregnant women and fetuses. Pregnant women should pay attention to their exposure to occupational noise to prevent gestational hypertension. The results of this study must be further verified and generalized.

A Personalized Anisotropic Margin for Cervical Cancer Radiation Therapy Under the Guidance of Daily Iterative Cone-Beam Computed Tomography (iCBCT).

Online adaptive radiation therapy (ART) eliminates interfraction uncertainties by adaption before each treatment session. However, intrafraction motions still exist and could become more severe due to long treatment time. Large isotropic margins can ensure clinical target volume (CTV) coverage but at the cost of more organs at risk damage. In this study, we proposed a novel personalized anisotropic margin search algorithm for cervical cancer radiation therapy under the guidance of daily iterative cone-beam computed tomography (iCBCT) to find the optimal margin values for each patient, which achieves the smallest possible planning target volume (PTV) and maintains CTV coverage. Twenty-two online Ethos ART treatment sessions were included for analysis. Two iCBCT scans were taken in each session. The first one (iCBCT1) was taken after positioning, and the second one (iCBCT2) was taken before beam delivery. Corresponding CTV1 and CTV2 were contoured in the two scans. In each session, minimal isotropic margins were first searched by iteratively increasing the magnitude until the resulting PTViso covers 99% of CTV2. Afterward, the margin values in all six directions were decreased iteratively until CTV2 coverage was smaller than 99% to get the personalized margin and target volume PTVint. In addition, the uterus was considered separately, and different margins were found for it and the remaining CTV, respectively, to reduce the target volume of PTVsep further. PTViso, PTVint, and PTVsep were compared in terms of CTV2 coverage and absolute volume. The algorithm successfully generated PTViso, PTVint, and PTVsep for all online ART treatment sessions. The mean ± SD values for PTViso 5mm, PTViso 10mm, PTViso 15mm, PTVint, and PTVsep were 1,074.0 ± 78.1, 1,519.5 ± 100.4, 2,006.4 ± 122.5, 929.3 ± 73.4, and 845.1 ± 72.5 mL, respectively. The volume difference between PTVint and PTVsep was significant (p < 0.001). All the PTVs ensured an average coverage larger than 99%, and the differences between any two PTVs were insignificant. This study proposed a novel personalized anisotropic margin search algorithm for cervical cancer online ART. Compared to the conventional 5 or 10 mm isotropic margins, the personalized anisotropic margin reduced PTV volume by 13.5% and 38.8%, respectively; if the uterus was considered separately, the volume can be further reduced by 21.3% and 44.3%, respectively, while CTV coverage was still maintained. This algorithm could reduce target volume and potentially spare normal tissue better than isotropic margin expansion.

Real-world outcomes of first-line maintenance therapy for recurrent or metastatic cervical cancer: A multi-center retrospective study.

BACKGROUND: Maintenance therapy (MT) for recurrent or metastatic cervical cancer remains non-standardized. This study assessed MT effectiveness using a comprehensive approach and identifies prognosis factors inpatients with recurrent or metastatic cervical cancer. METHODS: From January 2019 and December 2021, over 6000 patients from six Chinese institutions were retrospectively examined. Patients had recurrent/metastatic cervical cancer and underwent first-line chemotherapy with or without MT. We calculated overall and progression-free survival using Kaplan-Meier analysis, comparing via log-rank test, and conducted Cox regression for prognostic factors. RESULTS: Overall, 274 patients were stratified into an MT group (n = 77) and a non-MT group (n = 197). The 3-year OS rates were 52.5 % and 28.0 % for the MT and non-MT groups, respectively. The MT group had significantly enhanced median OS (37 vs. 21 months; HR, 0.43; 95 % CI, 0.30-0.61; P < 0.001) and PFS (21 vs. 14 months; HR, 0.65; 95 % CI, 0.47-0.90; P = 0.014) compared with the non-MT group. No significant differences in efficacy were observed among the various MT regimens, whether PD-1 monoclonal antibody, targeted therapeutic agents, or a combination of both. Extended PFS and OS were observed in patients receiving > 8 MT cycles. Multivariate analyses revealed that oligometastasis, MT, exclusive prior surgery (as opposed to combined surgery and radiotherapy), and extended interval before recurrence were independent OS predictors (P = 0.045, P < 0.001, P = 0.010, and P = 0.005, respectively); oligometastasis, concurrent radiotherapy, MT, and extended interval before recurrence were independent PFS predictors (P = 0.004, P = 0.007, P = 0.009, and P = 0.003). CONCLUSIONS: The MT integration markedly extended PFS and OS in patients diagnosed with recurrent or metastatic cervical cancer.

Resonant and non-resonant optimizations by multi-constraint quantum control theory in molecular rotational states.

It is a promising research for optimization of quantum gate in the field of quantum computation. We investigate the feasibility of implementing the single-qubit gate (Hadamard) in molecular rotational system. By applying the Multi-constraint quantum optimal control method, the excepted final states can be achieved based on the molecular rotational states both in resonant and non-resonant cases with the control pulses. The permanent electric dipole moment is ignored in non-resonance. Besides, the zero-pulse area constraint and the constant fluence constraint are employed to optimize shapes of control pulses. Finally, we show that the Hadamard gate can be realized with the high fidelity (0.9999) and also examine the dependence of the fidelity on pulse fluence as well as the control pulse.

Correlations between alterations of T-helper 17 cells and treatment efficacy after concurrent radiochemotherapy in locally advanced cervical cancer (stage IIB-IIIB): a 3-year prospective study.

BACKGROUND: Recently, T-helper 17 (Th17) cells have been proved to play an important role in promoting cervical cancer. But, till now, few study has been carried out to understand the involvement of these cells in efficacy of anti-tumor treatments. This study aimed to investigate the alterations in the percentage of circulating Th17 cells and related cytokines in locally advanced cervical cancer (LACC) patients before and after concurrent chemoradiotherapy (cCRT) and to analyze the correlations between the alterations in Th17 cells and treatment efficacy. METHODS: A prospective study with 49 LACC (International federation of gynecology and obstetrics [FIGO] stage IIB-IIIB) patients and 23 controls was conducted. Patients received the same cCRT schedule and were followed up for 3 years. Circulating Th17 cells (CD3+CD8- interleukin [IL]-17+ T cells) and related cytokines IL-17, transforming growth factor-ß (TGF-ß), IL-10, IL-23, IL-6, and IL-22 were detected before and after cCRT. Correlations between alterations of circulating Th17 cells and treatment efficacy were analyzed. Kaplan-Meier analysis was used for overall survival (OS) and progression-free survival (PFS). RESULTS: We found that 40 patients finished the entire cCRT schedule and met the endpoint of this study. The percentage of circulating Th17 cells in the LACC patients was higher than that in the controls, and it significantly decreased after cCRT (P < 0.05). After cCRT, patients were divided into two groups based on the average of the Th17 cells declined. The subgroup of patients with a prominent decrease in circulating Th17 cells after cCRT had a higher treatment efficacy and longer PFS and OS times. Compared with the control patients, LACC patients had higher IL-6, IL-10, IL-22, TGF-ß levels and a lower IL-23 level (P < 0.05). After cCRT, IL-6, IL-10, IL-17, IL-23 level significantly increased and TGF-ß level significantly decreased compared with the levels before cCRT (P < 0.05). CONCLUSION: Circulating Th17 cells in the LACC patients (FIGO stage IIB-IIIB) were higher than those in the controls, but they generally decreased after cCRT. A more pronounced decrease in circulating Th17 cells after cCRT was correlated with better therapeutic effect and longer PFS and OS times.

Apatinib combined with chemotherapy or concurrent chemo-brachytherapy in patients with recurrent or advanced cervical cancer: A phase 2, randomized controlled, prospective study.

OBJECTIVE: Apatinib mesylate is a novel vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitor, which has exhibited good safety and efficacy in several types of solid tumors. The present study aimed to assess the clinical efficacy and safety of apatinib combined with chemotherapy and concurrent chemo-brachytherapy (CCBT) in patients with recurrent and advanced cervical cancer. METHODS: A total of 52 patients with first diagnosed recurrent or untreated International Federation of Gynecology and Obstetrics stage IVB cervical cancer admitted at Shandong Cancer Hospital and Institute between July 2016 and May 2018 were analyzed in the current randomized controlled trial. The patients were randomly divided into 2 groups: the apatinib-treated group and the control group. Patients with recurrent cervical cancer in the apatinib-treated group were administered apatinib and carboplatin-paclitaxel as first-line chemotherapy. Patients with advanced cervical cancer were administered apatinib in combination with CCBT. In control group, patients with recurrent cervical cancer were treated with chemotherapy alone while patients with advanced cervical cancer received CCBT. RESULTS: The progression-free survival was significantly prolonged in apatinib group compared with control group (10.1 months; 95% confidence interval (CI), 8.42-11.79 vs 6.4 months; 95% CI, 3.88-8.92; P < .01; hazard ratio (HR), 0.44; 95% CI, 0.25-0.78; P < .01). The objective response rate in apatinib group was obviously higher than that in control group (64.3% vs 33.3%, P < .05). Proteinuria, hand-foot syndrome, mucositis, and hypertension in all Grades were statistically more common in apatinib group than in control group. Apatinib did not obviously aggravate other radiotherapy or chemotherapy side effects. CONCLUSION: Apatinib exhibited promising clinical efficacy in cervical cancer patients, resulting in an improved response rate and prolonged progression-free survival compared with the control group, and had manageable side effects. Our study revealed that apatinib combination therapy, adenocarcinoma, and bone metastasis.

Aberrant expression of hSef and Sprouty4 in endometrial adenocarcinoma.

Fibroblast growth factor (FGF) 2-mediated signaling of the mitogen-activated protein kinase/RAS/extracellular signal-regulated kinase 1/2 pathway is a critical modulator in angiogenesis and is therefore essential for the pathogenesis of endometrial carcinoma. Human similar expression to FGFs (hSef) and Sprouty4 have each been reported to be negative regulators of FGF signaling. The aim of the present study was to investigate the expression of hSef and Sprouty4 in human endometrial adenocarcinoma. Using immunohistochemistry analysis, the expression of hSef and Sprouty4 was detected in human endometrial adenocarcinomas. Increased hSef expression was found to be present in endometrial adenocarcinomas. In addition, decreased hSef expression was identified in the blood vessels of endometrial adenocarcinoma samples. However, the expression of Sprouty4 was downregulated in human endometrial adenocarcinoma. Aberrant expression of hSef and Sprouty4 are involved in the pathogenesis of human endometrial adenocarcinoma.

Dual-specificity phosphatase 6 (Dusp6), a negative regulator of FGF2/ERK1/2 signaling, enhances 17ß-estradiol-induced cell growth in endometrial adenocarcinoma cell.

Dual-specificity phosphatase 6 (Dusp6) is a negative feedback mechanism of fibroblast growth factors (FGFs)/mitogen-activated protein kinase (MAPK)/ERK1/2 signaling. The aim of this study was to explore the expression of Dusp6 in human endometrial adenocarcinomas and the role of Dusp6 expression in the growth regulation of endometrial adenocarcinoma cell. We found that Dusp6 was over-expressed in human endometrial adenocarcinomas. In Ishikawa cells, plasmid-driven Dusp6 expression efficiently blocked the activity of FGF2-induced MAPK/ERK1/2 signaling. Unexpectedly, Dusp6 expression significantly enhanced the growth of Ishikawa cells. In Dusp6 forced-expression cells, 17ß-estradiol stimulation increased the cell growth by all most threefolds. In addition, progesterone treatment reduced the cell growth to about half both in Ishikawa cells with and without forced-Dusp6-expression. Dusp6 over-expression is involved in the pathogenesis and development of human endometrial adenocarcinomas. Dusp6 functions as a negative regulator of FGF2/ERK1/2 signaling but enhances the growth and 17ß-estradiol-induced cell growth in endometrial adenocarcinoma cell.