CA125 over-release behavior following a 75-g oral glucose test as a predictive biomarker of multidrug resistance in patients with ovarian cancer.

Multidrug resistance is a major cause of death in patients with ovarian cancer. To improve patient survival, we developed a novel, noninvasive and convenient tool, the 75-gram oral glucose (75gOG)-stimulated CA125 test, to monitor cancer chemoresistance in real time. Our in vitro proof-of-principal experiments revealed that post-75gOG glucose and insulin peaks can synergistically increase cancer-derived CA125 levels, and the increase in CA125 secretion (ΔCA125) is correlated with the overactivation of the insulin receptor (IR)-PI3K-Akt axis and increases (ΔIC50 s) in cisplatin/taxol IC50 s. Correspondingly, among the 93 patients enrolled, post-75gOG CA125 over-release (i.e., enhanced ΔCA125) behavior was associated with overexpression of the IR-PI3K-Akt pathway and its downstream components, namely, IR, pAkt, pS6 and GLUT4, in cancer specimens. Furthermore, both pre- and postsurgical 75gOG CA125 tests demonstrated that CA125 over-release showed excellent prediction efficacy on the chemoresistance potential of ovarian cancer; notably, the former indicated the need for an optimal debulking surgery, and the latter suggested the use of IR-PI3K-Akt inhibitors. Both test results possess independent prognostic significance for the 2-year progression-free survival (PFS) and overall survival (OS) of patients. The odds ratios and corresponding 95% confidence intervals (95% CIs) were 2.680 (95% CI: 1.393-5.156) for patients with CA125 over-release behavior evidenced by a presurgical 75gOG CA125 test or 3.822 (95% CI: 1.942-7.522) for that evidenced by a postsurgical test in PFS; and 3.320 (95% CI: 1.508-7.309) for patients with CA125 over-release behavior evidenced by a presurgical test or 5.212 (95% CI: 2.241-12.121) for that evidenced by a postsurgical test in OS.

Postprandial increase in serum CA125 as a surrogate biomarker for early diagnosis of ovarian cancer.

BACKGROUND: CA125 is a prevalently used serum biomarker for detecting ovarian cancer over the last three decades. However, it has a significant deficiency in screening for early-stage cancer. With the purpose of exploring an effective approach to improve its performance in early diagnosis, we investigated the postprandial fluctuation pattern of cancer-derived CA125 and the underlying mechanism. METHODS: In two medical centers, 551 patients sonographically diagnosed with ovarian (adnexal) cysts (< 5 cm in diameter) were enrolled and divided into five disease groups (pelvic inflammatory cysts, retention cysts, endometrioma, benign/borderline cystadenoma and malignant cysts). The subtle differences in 1-h postprandial serum CA125 increases were compared between disease groups. A support vector machine (SVM)-based algorithm was used for refining the performance of CA125 postprandial increment. Ovarian cancer xenograft animal and cancer cell models were used to recapitulate the clinical findings and reveal the molecular basis of postprandial blood glucose and insulin in invoking the synthesis/secretion/re-absorption of CA125. RESULTS: Patients with ovarian cancer presented the highest postprandial increment 13.3 ± 0.7% (mean ± standard deviation) among the five disease groups. Using a CA125 increment ≥ 10% criterion, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) reached 83.3, 96.3, 61.1 and 98.8%, respectively, for early-stage ovarian cancer. This performance was further improved by the SVM-based CA125-increment algorithm, which exhibited 91.7% sensitivity, 99.2% specificity, 89.2% PPV and 99.4% NPV. Both modalities manifested diagnostic advantages over the traditional CA125 test (75.0% sensitivity, 25.4% specificity, 6.6% PPV and 93.6% NPV at the cut-off of 35 U/mL). Regarding the molecular basis, the postprandial blood glucose and insulin-invoked overexpression of Mucin 16 (encoding CA125) were demonstrated in animal and cancer cell models, which were mediated by the PI3K-Akt pathway. Nevertheless, a Mesothelin-based CA125 re-absorption behavior was noted in the treated cancer cells, which contributed to the over-drop following the postprandial peak of serum CA125. CONCLUSIONS: Cancer-derived serum CA125 possesses a unique and distinctive postprandial pattern, that distinguishes it from the common CA125 elevation in a benign disease condition. The dynamic measurement/assessment strategy can achieve a discriminatory power superior to that of a static test.

Polymorphisms of the interleukin 6 gene and additional gene-gene interaction contribute to cervical cancer susceptibility in Eastern Chinese women.

PURPOSE: To investigate the association between IL-6 gene polymorphism and cervical cancer risk, and the impact of multiple gene-gene interaction on cervical cancer risk based on a Chinese Han population. METHODS: A total of 1088 women were selected, including 360 cervical cancer patients and 728 control subjects. Logistic regression model was used to examine the association between SNPs within IL-6 and cervical cancer risk. Odds ratio (OR) and 95 % confident interval (95 % CI) were calculated. Generalized multifactor dimensionality reduction (GMDR) was employed to analyze the gene-gene interaction. RESULTS: Cervical cancer risks were significantly higher in carriers of C allele of rs1800795 polymorphism than those with GG genotype (GC+CC versus GG), adjusted OR (95 % CI) 1.60 (1.24-2.19), and also significantly higher in carriers of G allele of rs2069837 polymorphism than those with AA (AG+GG versus AA), adjusted OR (95 % CI) 1.49 (1.19-2.07). GMDR analysis found a significant gene-gene interaction between rs1800795 and rs2069837 (p = 0.0010). Overall, the two-locus models had a cross-validation consistency of 10 of 10, and had the testing accuracy of 61.72 %. We also calculated the odds ratios and 95 % CI for this interaction, and we found that subjects with GC or CC of rs1800795 and AG or GG of rs2069837 genotype have the highest cervical cancer risk, compared to subjects with GG of rs1800795 and AA of rs2069837 genotype, OR (95 % CI) 3.35 (2.01-4.78). CONCLUSIONS: Minor allele of rs1800795 and rs2069837 and its interaction were associated with increased cervical cancer risk.

Enhanced photovoltaic performance of CH3NH3PbI3 perovskite solar cells through interfacial engineering using self-assembling monolayer.

Morphology control is critical to achieve high efficiency CH3NH3PbI3 perovskite solar cells (PSC). The surface properties of the substrates on which crystalline perovskite thin films form are expected to affect greatly the crystallization and, thus, the resulting morphology. However, this topic is seldom examined in PSC. Here we developed a facile but efficient method of modifying the ZnO-coated substrates with 3-aminopropanioc acid (C3-SAM) to direct the crystalline evolution and achieve the optimal morphology of CH3NH3PbI3 perovskite film. With incorporation of the C3-SAM, highly crystalline CH3NH3PbI3 films were formed with reduced pin-holes and trap states density. In addition, the work function of the cathode was better aligned with the conduction band minimum of perovskite for efficient charge extraction and electronic coupling. As a result, the PSC performance remarkably increased from 9.81(±0.99)% (best 11.96%) to 14.25(±0.61)% (best 15.67%). We stress the importance of morphology control through substrate surface modification to obtain the optimal morphology and device performance of PSC, which should generate an impact on developing highly efficient PSC and future commercialization.

Aberrant HPO Axis Alterations and Autoimmune Abnormalities in PCOS Patients with DOR: A Retrospective Analysis.

BACKGROUND: There is a group of polycystic ovary syndrome (PCOS) patients in clinic who have diminished ovarian reserve (DOR) in combination. This study was designed to evaluate the differences in glucolipid metabolism, hypothalamic-pituitary-ovarian (HPO) axis-related parameters, and autoimmune antibodies in PCOS patients with and without DOR. METHODS: A total of 2307 PCOS patients, including 1757 patients with PCOS alone and 550 patients who have both PCOS and DOR, were enrolled in this retrospective study. Parameters of glucolipid metabolism, HPO axis-related parameters, and autoimmune antibodies were measured and analyzed. RESULTS: The prevalence of DOR among all patients with PCOS was 23.84%. Many HPO axis-related parameters, such as follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), and prolactin (PRL) were significantly different in PCOS with DOR compared with PCOS without DOR. The FSH levels were positively correlated with LH, testosterone (T), and androstenedione (AD) levels, but had no association with glucolipid metabolism after adjusting for body mass index (BMI). Moreover, anti-ovarian antibody (AOAb) and anti-21-OH antibody (21-OHAb) levels were significantly elevated in PCOS patients with DOR. CONCLUSIONS: PCOS patients with DOR showed more chaotic HPO axis hormone levels and elevated autoimmune antibodies, suggesting that autoimmune factors may be the cause of DOR in women with PCOS.

Tracking interface position of a high-speed imploding composite liner based on magnetic diffusion difference.

A technique for tracking the interface position of non-metal-metal composite liners during high-speed implosion is proposed in this paper. Based on the magnetic diffusion difference between metal and non-metal, the interface position information is obtained by measuring magnetic fields in the cavity of the liner. An efficient magnetic flux estimation algorithm based on iterative magnetic diffusion simulation is also proposed to estimate the magnetic flux loss of the liner. Numerical experiments show that the estimation algorithm can reduce the relative error to less than 0.5%. The composite solid liner experimental results show that the maximum error is about 2% under imperfect experimental conditions. Detailed analysis suggests that this method can be widely applied to non-metallic sample materials (electrical conductivity is less than 103 ∼ 104 S/m). The technique provides a useful supplement to the existing interface diagnosis methods for high-speed implosion liners.

1,3-Pentadiene-Assistant Living Anionic Terpolymerization: Composition Impact on Kinetics and Microstructure Sequence Primary Analysis.

The combination of a living anionic technology and a unique alternating strategy provided an exciting opportunity to prepare novel and well-defined poly(1,3-pentadiene-co-syrene-co-1,1-diphenylethylene) resins consisting of three alternating sequences of modules (A/B/C zwitterions). "A" being Styrene (St)/1,3-pentadiene (PD), "B" being diphenylethylene (DPE)/PD, "A" being DPE/St, respectively, A wide composition range of new polyolefin resins, i.e., poly (A-co-B), poly (A-co-C), and poly (B-co-C), with controlled molecular weight and very narrow molecular weight and composition distributions have been prepared by a one-pot living characteristic method. In the section of kinetic analysis, the terpolymer yields and kinetic parameters were strongly dependent on the feed/comonomer ratio as well as the content of the alternating structure. The competition copolymerization behaviors of A/B, B/C, and A/C were studied in detail in this work. By contrast, the microstructure and the thermal property of the resulting terpolymer were investigated via Nuclear magnetic resonance (NMR) and Differential scanning calorimetry (DSC) analysis. The results of 1H NMR tracking the change of [Aromatic ring]/[C=C] value indicated the distinctive copolymer-ization behavior of the selective "alternating-modules". The glass transition temperature (Tg) was very sensitive to the terpolymer composition. By contrast to poly(A-ran-B) with only one obvious Tg, there were two Tgs in the A/C and B/C copolymerization cases. Moreover, the desirable high Tg ~ 140 °C resin was limited to the terpolymers with up to 50 mol % DPE. Finally, the "ABC-X" mechanism was proposed to interpret the unique terpolymerization behavior, which belongs to the classical "bond-forming initiation" theory.

Development of a transient complex impedance measurement device used in quasi-isentropic compression experiments.

A complex impedance measurement device with a short response time and high noise immunity is presented in this paper. The device based on a radio-frequency reflectometer was specially developed for electro-physical property investigations of materials in quasi-isentropic compression experiments. The maximum operating frequency of the device is up to 600 MHz for reducing intense low-frequency noises. Meanwhile, an off-line signal processing code was developed to improve the response time of the device to less than 10 ns. Using the device, the complex impedance and electrical conductivity of water compressed by an explosive-driven magnetic flux compression generator were measured, and an abrupt change in the complex impedance of water caused by a liquid-solid transition was directly observed under intense electromagnetic interference.

Endocrinological and metabolic characteristics in patients who are non-obese and have polycystic ovary syndrome and different types of a family history of type 2 diabetes mellitus.

OBJECTIVE: We aimed to investigate whether patients with polycystic ovary syndrome (PCOS) and a family history (FH) of type 2 diabetes mellitus (T2DM) are at increased risk of endocrinological and metabolic abnormalities, and whether this risk differs between first-degree and second-degree relatives, and between maternal and paternal transmission. METHODS: A total of 680 patients with PCOS were enrolled in this retrospective, single-center study. Endocrine and glycolipid metabolism parameters were compared. RESULTS: The free androgen index (FAI), and levels of fasting blood glucose (FBG), fasting insulin (FINS), homeostatic model assessment-insulin resistance (HOMA-IR), total cholesterol (TC), and low-density lipoprotein cholesterol were significantly higher, whereas sex hormone binding globulin (SHBG) levels were significantly lower in patients with PCOS and a FH of T2DM. In patients with PCOS with a FH of T2DM in first-degree relatives, age and levels of FBG, FINS, and HOMA-IR were significantly higher than those who had a FH of T2DM in second-degree relatives. A maternal history of T2DM was associated with a higher body mass index, FAI, and TG levels, and lower SHBG levels. CONCLUSIONS: Patients with PCOS and a FH of T2DM have more severe hyperandrogenism and metabolic disorders, especially in those with maternal transmission.

Ratiometric Raman nanotags enable intraoperative detection of metastatic sentinel lymph node.

Sentinel lymph node (SLN) imaging and biopsy has been advocated as an important technique to evaluate the metastatic status of regional lymph nodes and determine subsequent surgical procedure for many cancers, yet there is no reliable means to provide accurate and rapid diagnosis of metastatic SLN during surgery. Here we develop a new approach, named "Ratiometric Raman dual-nanotag strategy", that using folic acid functionalized targeted and nontargeted gap-enhanced Raman tags (FA-GERTs and Nt-GERTs) to detect metastatic SLN based on Raman imaging combined with classical least square data processing methods. By using this strategy, with built-in self-calibration for signal correction, rather than absolute intensity-dependent signal readout, we realize the visualization and prompt intraoperative diagnosis of metastatic SLN with a high accuracy of 87.5 % when the cut-off value of ratio (FA-GERTs/Nt-GERTs) set at 1.255. This approach may outperform the existing histopathological assessment in diagnosing SLN metastasis and is promising for guiding surgical procedure in the future.

A compact platform for the investigation of material dynamics in quasi-isentropic compression to ~ 19 GPa.

This paper reports on the development of a magnetically driven high-velocity implosion experiment conducted on the CQ-3 facility, a compact pulsed power generator with a load current of 2.1 MA. The current generates a high Lorentz force between inner and outer liners made from 2024 aluminum. Equally positioned photonic Doppler velocimetry probes record the liner velocities. In experiment CQ3-Shot137, the inner liner imploded with a radial converging velocity of 6.57 km/s while the outer liner expanded at a much lower velocity. One-dimensional magneto-hydrodynamics simulation with proper material models provided curves of velocity versus time that agree well with the experimental measurements. Simulation then shows that the inner liner underwent a shock-less compression to approximately 19 GPa and reached an off-Hugoniot high-pressure state. According to the scaling law that the maximum loading pressure is proportional to the square of the load current amplitude, the results demonstrate that such a compact capacitor bank as CQ-3 has the potential to generate pressure as high as 100 GPa within the inner liner in such an implosion experiment. It is emphasized that the technique described in this paper can be easily replicated at low cost.

Epigenetic heterogeneity promotes acquired resistance to BET bromodomain inhibition in ovarian cancer.

BET bromodomain inhibitors (BETi) are promising therapeutic regimens for epithelial ovarian cancer (EOC). However, early-stage clinical trials indicate that drug tolerance may limit their anti-tumor efficacy. Here, we show that JQ1-refractory EOC cells acquire reversible resistance to BET inhibition and remain dependent on BRD4 function. The insensitivity is driven by a unique non-genetic mechanism that involves clonal selection for a pre-existing cell subpopulation with ample acetylated histones and sufficient nuclear phase-separated BRD4 droplets to counteract BETi antagonism. A vertical combination approach by co-blocking BET proteins and downstream Aurora kinases proves to achieve more complete responses than single inhibitors. Collectively, our study implicates epigenetic heterogeneity in therapeutic resistance to chromatin-targeted agents and proposes a rational strategy to address this anticipated clinical dilemma.

Hydrogen Clathrate Structures in Uranium Hydrides at High Pressures.

Room-temperature superconductivity has always been an area of intensive research. Recent findings of clathrate metal hydrides structures have opened up the doors for achieving room-temperature superconductivity in these materials. Here, we report first-principles calculations for stable H-rich clathrate structures of uranium hydrides at high pressures. The clathrate uranium hydrides contain H cages with stoichiometries of H24, H29, and H32, in which H atoms are bonded covalently to other H atoms, and U atoms occupy the centers of the cages. Especially, a UH10 clathrate structure containing H32 cages is predicted to have an estimated T c higher than 77 K at high pressures.

ALKBH5 regulates IGF1R expression to promote the Proliferation and Tumorigenicity of Endometrial Cancer.

N6-methyladenosine (m6A) messenger RNA methylation play important role in cell proliferation and tumorigenicity of endometrial cancer, but the key mechanism is not fully clear. Here, we found that RNA demethylase ALKBH5 expression was significantly upregulated in endometrial cancer, ALKBH5 was then identified to positively regulate proliferation and invasion of endometrial cancer. Mechanistically, the m6A eraser ALKBH5 demethylated target transcripts IGF1R and enhanced IGF1R mRNA stability, consequently promoting IGF1R translation and activating IGF1R signaling pathway. Thus, we demonstrated that ALKBH5 promoted proliferation and invasion of endometrial cancer via erasing IGF1R m6A-modifications, which suggests a potential therapeutic target for endometrial cancer.

Temperature effect on the phase stability of hydrogen C2/c phase from first-principles molecular dynamics calculations.

The structural stability of hydrogen C2/c phase from 0 K to 300 K is investigated by combining the first-principles molecular dynamics (MD) simulations and density functional perturbation theory. Without considering the temperature effect, the C2/c phase is stable from 150 GPa to 250 GPa based on the harmonic phonon dispersion relations. The hydrogen molecules at the solid lattice sites are sensitive to temperature. The structural stability to instability transition of the C2/c phase upon temperature is successfully captured by the radial distribution function and probability distribution of atomic displacements from first-principles MD simulations, confirmed by the phonon power spectrum analysis in the phase space. The existence of phonon quasiparticle for different normal modes is observed directly. The phonon power spectrum of specific normal modes corresponding to the Raman and infrared (IR) activations are depicted at different temperatures and pressures. The changes of frequency with temperature are in agreement with experimental results, supporting the C2/c as the hydrogen phase III. For the first time, the anharmonic phonon dispersion curves and density of states are predicted based on the phonon quasi-particle approach. Therefore, the temperature dependence of lattice vibrations can be observed directly, providing a more complete physical picture of phonon frequency distribution with respect to the Raman and IR spectra. It is found that the high-frequency regions adopt significant frequency shifts compared to the harmonic case.

MiR-1180 from bone marrow-derived mesenchymal stem cells induces glycolysis and chemoresistance in ovarian cancer cells by upregulating the Wnt signaling pathway.

BACKGROUND: Bone marrow-derived mesenchymal stem cells (BM-MSCs) play an important role in cancer development and progression. However, the mechanism by which they enhance the chemoresistance of ovarian cancer is unknown. METHODS: Conditioned media of BM-MSCs (BM-MSC-CM) were analyzed using a technique based on microRNA arrays. The most highly expressed microRNAs were selected for testing their effects on glycolysis and chemoresistance in SKOV3 and COC1 ovarian cancer cells. The targeted gene and related signaling pathway were investigated using in silico analysis and in vitro cancer cell models. Kaplan-Merier survival analysis was performed on a population of 59 patients enrolled to analyze the clinical significance of microRNA findings in the prognosis of ovarian cancer. RESULTS: MiR-1180 was the most abundant microRNA detected in BM-MSC-CM, which simultaneously induces glycolysis and chemoresistance (against cisplatin) in ovarian cancer cells. The secreted frizzled-related protein 1 (SFRP1) gene was identified as a major target of miR-1180. The overexpression of miR-1180 led to the activation of Wnt signaling and its downstream components, namely Wnt5a, ß-catenin, c-Myc, and CyclinD1, which are responsible for glycolysis-induced chemoresistance. The miR-1180 level was inversely correlated with SFRP1 mRNA expression in ovarian cancer tissue. The overexpressed miR-1180 was associated with a poor prognosis for the long-term (96-month) survival of ovarian cancer patients. CONCLUSIONS: BM-MSCs enhance the chemoresistance of ovarian cancer by releasing miR-1180. The released miR-1180 activates the Wnt signaling pathway in cancer cells by targeting SFRP1. The enhanced Wnt signaling upregulates the glycolytic level (i.e. Warburg effect), which reinforces the chemoresistance property of ovarian cancer cells.

A VEGF-dependent gene signature enriched in mesenchymal ovarian cancer predicts patient prognosis.

We have previously reported surrogate biomarkers of VEGF pathway activities with the potential to provide predictive information for anti-VEGF therapies. The aim of this study was to systematically evaluate a new VEGF-dependent gene signature (VDGs) in relation to molecular subtypes of ovarian cancer and patient prognosis. Using microarray profiling and cross-species analysis, we identified 140-gene mouse VDGs and corresponding 139-gene human VDGs, which displayed enrichment of vasculature and basement membrane genes. In patients who received bevacizumab therapy and showed partial response, the expressions of VDGs (summarized to yield VDGs scores) were markedly decreased in post-treatment biopsies compared with pre-treatment baselines. In contrast, VDGs scores were not significantly altered following bevacizumab treatment in patients with stable or progressive disease. Analysis of VDGs in ovarian cancer showed that VDGs as a prognostic signature was able to predict patient outcome. Correlation estimation of VDGs scores and molecular features revealed that VDGs was overrepresented in mesenchymal subtype and BRCA mutation carriers. These findings highlighted the prognostic role of VEGF-mediated angiogenesis in ovarian cancer, and proposed a VEGF-dependent gene signature as a molecular basis for developing novel diagnostic strategies to aid patient selection for VEGF-targeted agents.