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Epigenetic alterations have been functionally linked to ovarian cancer development and occurrence. The CXXC zinc finger protein 1 (CFP1) is an epigenetic regulator involved in DNA methylation and histone modification in mammalian cells. However, its role in ovarian cancer cells is unknown. Here, we show that CFP1 protein is highly expressed in human ovarian cancer tissues. Loss of CFP1 inhibited the growth of human ovarian cancer cells, promoted apoptosis, and increased senescence. CFP1 knockdown resulted in reduced levels of SETD1 (a CFP1 partner) and histone H3 trimethylation at the fourth lysine residue (H3K4me3). RNA-sequencing revealed that deletion of CFP1 resulted in mRNA reduction of bone marrow stromal cell antigen 2 (BST2). Bioinformatics analysis and chromatin immunoprecipitation showed that CFP1 binds to the promoter of BST2 and regulates its transcription directly. Overexpression of BST2 rescued the growth inhibitory effect of CFP1 loss. Furthermore, depletion of cullin-RING ubiquitin ligases 4 (CRL4) components ROC1 or CUL4A had significantly inhibited the expression of CFP1 and BST2 similar to MLN4924 treatment that blocked cullin neddylation and inactivated CRL4s. In conclusion, CFP1 promotes ovarian cancer cell proliferation and apoptosis by regulating the transcription of BST2, and the expression of CFP1 was affected by CRL4 ubiquitin ligase complex.

Cell senescence deters the activation of various oncogenes. Induction of senescence is therefore a potentially effective strategy to interfere with vital processes in tumor cells. Sphingosine-1-phosphate receptor 1 (S1PR1) has been implicated in various cancer types, including ovarian cancer. The mechanism by which S1PR1 regulates ovarian cancer cell senescence is currently elusive. In this study we demonstrate that S1PR1 was highly expressed in human ovarian cancer tissues and cell lines. S1PR1 deletion inhibited the proliferation and migration of ovarian cancer cells, which concurred with cell cycle arrest in the G1/S phase. S1PR1 deletion enhanced cisplatin-induced ovarian cancer cell senescence. Treatment of ovarian cancer cells with sphingosine-1-phosphate (S1P) led to increased expression of 3-phosphatidylinositol-dependent protein kinase 1 (PDK1), decreased expression of large tumor suppressor 1/2 (LATS1/2), and increased activity of the yes-associated protein (YAP). Opposite results were obtained in S1PR1-knockout or pharmacological inhibition in ovarian cancer cells. LATS1/2 inactivation caused by S1PR1 deletion increased YAP expression, inhibited senescence, and lead to increased S1PR1 expression. Transcriptional regulation of S1PR1 by YAP was confirmed by chromatin immunoprecipitation. Accordingly, the S1PR1-PDK1-LATS1/2-YAP pathway regulates ovarian cancer cell senescence and does so through a YAP-mediated feedback loop. S1PR1 constitutes a druggable target for the induction of senescence in ovarian cancer cells. Pharmacological intervention in the S1PR1-PDK1-LATS1/2-YAP signaling axis may augment the efficacy of standard chemotherapy.

Background: Anti-PD-L1/VEGF inhibition, coupled with chemotherapy, may potentiate antitumor immunity leading to enhanced clinical benefit, but it has not been investigated in advanced biliary tract cancer (BTC). We investigated the efficacy and safety of gemcitabine plus oxaliplatin (GEMOX) combined with atezolizumab and bevacizumab for advanced BTC and explore the potential biomarkers related with response. Patients and Methods: Advanced BTC patients, who received a triple combination therapy at three medical centers between March 18th, 2020 and Sep 1st, 2021, were included. Treatment response was evaluated via mRECIST and RECIST v1.1. Endpoints included the overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. The whole exome sequencing of pathological tissues was conducted for bioinformatic analysis. Results: Thirty patients were enrolled ultimately in this study. The best ORR was 76.7% and the disease control rate was 90.0%. The median PFS was 12.0 months, and the median OS was not reached. During the treatment, 10.0% (3/30) patients suffered from ≥ grade 3 treatment-related adverse events (TRAEs). Furthermore, fever (73.3%), neutropenia (63.3%), AST and ALT level increased (50.0% and 43.3% respectively) are the most common TRAEs. Bioinformatics analysis revealed patients with altered ALS2CL had a higher ORR. Conclusion: The triple combination of atezolizumab, bevacizumab and GEMOX is potentially efficacious and safe for patients with advanced BTC. The mutation of ALS2CL is a potential predictive biomarker for the efficacy of triple combination therapy.

Background: The immune checkpoint ligand, programmed cell death 1 ligand 1 (PD-L1), is expressed in various tumors and associated with response to drugs that target programmed cell death protein 1. Previous studies have estimated the level of PD-L1 expression among different stages of thymoma and thymic carcinoma to evaluate its potential use as a diagnostic factor; however, its varying expression level has been problematic. We conducted this meta-analysis of published literature to evaluate PD-L1 expression in thymomas and thymic carcinomas. Methods: We analyzed 12 studies that included 320 patients with type A/AB/B1 thymoma, 225 patients with type B2/B3 thymoma, and 180 patients with thymic carcinoma. Results: No difference in PD-L1 expression level was found between the B2/B3 vs C groups (odds ratio [OR], 0.67; 95% confidence interval [CI], 0.26, 1.76; p = 0.42). However, the heterogeneity was very high ( I2 = 78%), and a significant difference was found between groups A/AB/B1 and B2/B3 (OR, 0.22; 95% CI, 0.12, 0.41; p < 0.001), with a relatively low heterogeneity ( I2 = 55%). Conclusion: PD-L1 positivity might be a useful factor to differentiate type A/AB/B1 thymoma from type B2/B3 and thymic carcinoma. This result might be valuable for potential anti PD-L1 treatment in thymoma and thymic carcinoma.

Background: Whether or not EGFR mutation status detected by ddPCR in plasma predicts the effect of icotinib on patients with advanced lung adenocarcinoma was determined. Methods: Plasma and matched tissue specimens from patients with advanced lung adenocarcinoma were collected prior to icotinib treatment. The ARMS method was used to detect EGFR mutation status in DNA extracted from tissue specimens, while the EGFR mutation status in ctDNA extracted from plasma specimens was determined by ddPCR. The therapeutic effects of icotinib were compared between patients with EGFR - activating mutations detected by ddPCR in ctDNA and ARMS in tissue DNA. Results: EGFR mutation status was detected in 96 tissue and 100 plasma specimens. The sensitivity and positive predictive value of 19del detected in ctDNA by ddPCR was 70.97% (22/31) and 44.90% (22/49), respectively. The positive predictive value was 84.62% (22/26) and the sensitivity was 53.66% (22/41) for the L858R mutation. For the common sensitive EGFR mutations, ddPCR had a positive predictive value of 77.19% (44/57) and a sensitivity of 48.89% (44/90). Patients with sensitive EGFR mutations in ctDNA had objective response and disease control rates (DCR) similar to patients who had sensitive EGFR mutations in tissues detected by ARMS when treated with icotinib (57.14% vs . 51.51% and 92.86% vs . 90.91%, respectively). Conclusions: Patients with sensitive EGFR mutations in plasma specimens detected with ddPCR had a higher ORR and DCR compared with patients with sensitive EGFR mutations in tissue detected with the ARMS method.

OBJECTIVE: To investigate the incidence rate and risk factors for metabolic bone disease of prematurity (MBDP) in very low birth weight/extremely low birth weight (VLBW/ELBW) infants. METHODS: The medical data of 61 786 neonates from multiple centers of China between September 1, 2013 and August 31, 2016 were retrospectively investigated, including 504 VLBW/ELBW preterm infants who met the inclusion criteria. Among the 504 infants, 108 infants diagnosed with MBDP were enrolled as the MBDP group and the remaining 396 infants were enrolled as the non-MBDP group. The two groups were compared in terms of general information of mothers and preterm infants, major diseases during hospitalization, nutritional support strategies, and other treatment conditions. The multivariate logistic regression analysis was used to investigate the risk factors for MBDP. RESULTS: The incidence rate of MBDP was 19.4% (88/452) in VLBW preterm infants and 38.5% (20/52) in ELBW preterm infants. The incidence rate of MBDP was 21.7% in preterm infants with a gestational age of < 32 weeks and 45.5% in those with a gestational age of < 28 weeks. The univariate analysis showed that compared with the non-MBDP group, the MBDP group had significantly lower gestational age and birth weight, a significantly longer length of hospital stay, and a significantly higher incidence rate of extrauterine growth retardation (P < 0.05). Compared with the non-MBDP group, the MBDP group had significantly higher incidence rates of neonatal sepsis, anemia, hypocalcemia, and retinopathy of prematurity (P < 0.05). The MBDP group had a significantly lower mean feeding speed, a significantly higher age when reaching total enteral feeding, and a significantly longer duration of parenteral nutrition (P < 0.05). The use rate of caffeine citrate in the MBDP group was significantly higher, but the use rate of erythropoietin was significantly lower than that in the non-MBDP group (P < 0.05). The multivariate logistic regression analysis showed that gestational age < 32 weeks, hypocalcemia, extrauterine growth retardation at discharge, and neonatal sepsis were risk factors for MBDP (P < 0.05). CONCLUSIONS: A lower gestational age, hypocalcemia, extrauterine growth retardation at discharge, and neonatal sepsis may be associated an increased risk of MBDP in VLBW/ELBW preterm infants. It is necessary to strengthen perinatal healthcare, avoid premature delivery, improve the awareness of the prevention and treatment of MBDP among neonatal pediatricians, and adopt positive and reasonable nutrition strategies and comprehensive management measures for preterm infants.

While the existence of disorders is commonly believed to weaken the unique properties of quantum systems, recent progress has predicted that it can exhibit a counterintuitive enhanced effect on the behavior of entanglement generation, which is even independent of the chosen initial conditions and physical platforms. However, to achieve a maximally entangled state in such disordered quantum systems, the key limitation of this is the scarcity of an infinite coherence time, which makes its experimental realization challenging. Here, we experimentally investigate the entanglement entropy dynamics in a photonic quantum walk with disorders in time. Through the incorporation of a classic optimization algorithm, we experimentally demonstrate that such disordered systems can relax to a high-entanglement hybrid state at any given time step. Moreover, this prominent entangling ability is universal for a wide variety of initial conditions. Our results may inspire achieving a well-controlled entanglement generator for quantum computation and information tasks.

Background and aim Oncological photodynamic therapy (PDT) relies on photosensitizers (PSs) to photo-oxidatively destroy tumor cells. Currently approved PSs yield satisfactory results in superficial and easy-to-access tumors but are less suited for solid cancers in internal organs such as the biliary system and the pancreas. For these malignancies, second-generation PSs such as metallated phthalocyanines are more appropriate. Presently it is not known which of the commonly employed metallated phtahlocyanines, namely aluminum phthalocyanine (AlPC) and zinc phthalocyanine (ZnPC) as well as their tetrasulfonated derivatives AlPCS4 and ZnPCS4, is most cytotoxic to tumor cells. This study therefore employed an attritional approach to ascertain the best metallated phthalocyanine for oncological PDT in a head-to-head comparative analysis and standardized experimental design. Methods ZnPC and AlPC were encapsulated in PEGylated liposomes. Analyses were performed in cultured A431 cells as a template for tumor cells with a dysfunctional P53 tumor suppressor gene and EGFR overexpression. First, dark toxicity was assessed as a function of PS concentration using the WST-1 and sulforhodamine B assay. Second, time-dependent uptake and intracellular distribution were determined by flow cytometry and confocal microscopy, respectively, using the intrinsic fluorescence of the PSs. Third, the LC50 values were established for each PS at 671 nm and a radiant exposure of 15 J/cm2 following 1-h PS exposure. Finally, the mode of cell death as a function of post-PDT time and cell cycle arrest at 24 h after PDT were analyzed. Results In the absence of illumination, AlPC and ZnPC were not toxic to cells up to a 1.5-μM PS concentration and exposure for up to 72 h. Dark toxicity was noted for AlPCS4 at 5 μM and ZnPCS4 at 2.5 μM. Uptake of all PSs was observed as early as 1 min after PS addition to cells and increased in amplitude during a 2-h incubation period. After 60 min, the entire non-nuclear space of the cell was photosensitized, with PS accumulation in multiple subcellular structures, especially in case of AlPC and AlPCS4. PDT of cells photosensitized with ZnPC, AlPC, and AlPCS4 yielded LC50 values of 0.13 μM, 0.04 μM, and 0.81 μM, respectively, 24 h post-PDT (based on sulforhodamine B assay). ZnPCS4 did not induce notable phototoxicity, which was echoed in the mode of cell death and cell cycle arrest data. At 4 h post-PDT, the mode of cell death comprised mainly apoptosis for ZnPC and AlPC, the extent of which was gradually exacerbated in AlPC-photosensitized cells during 8 h. ZnPC-treated cells seemed to recover at 8 h post-PDT compared to 4 h post-PDT, which had been observed before in another cell line. AlPCS4 induced considerable necrosis in addition to apoptosis, whereby most of the cell death had already manifested at 2 h after PDT. During the course of 8 h, necrotic cell death transitioned into mainly late apoptotic cell death. Cell death signaling coincided with a reduction in cells in the G0/G1 phase (ZnPC, AlPC, AlPCS4) and cell cycle arrest in the S-phase (ZnPC, AlPC, AlPCS4) and G2 phase (ZnPC and AlPC). Cell cycle arrest was most profound in cells that had been photosensitized with AlPC and subjected to PDT. Conclusions Liposomal AlPC is the most potent PS for oncological PDT, whereas ZnPCS4 was photodynamically inert in A431 cells. AlPC did not induce dark toxicity at PS concentrations of up to 1.5 μM, i.e., > 37 times the LC50 value, which is favorable in terms of clinical phototoxicity issues. AlPC photosensitized multiple intracellular loci, which was associated with extensive, irreversible cell death signaling that is expected to benefit treatment efficacy and possibly immunological long-term tumor control, granted that sufficient AlPC will reach the tumor in vivo. Given the differential pharmacokinetics, intracellular distribution, and cell death dynamics, liposomal AlPC may be combined with AlPCS4 in a PS cocktail to further improve PDT efficacy.

The concept of supersymmetry developed in particle physics has been applied to various fields of modern physics. In quantum mechanics, the supersymmetric systems refer to the systems involving two supersymmetric partner Hamiltonians, whose energy levels are degeneracy except one of the systems has an extra ground state possibly, and the eigenstates of the partner systems can be mapped onto each other. Recently, an interferometric scheme has been proposed to show this relationship in ultracold atoms [Phys. Rev.A 96, 043624 (2017)]. Here this approach is generalized to linear optics for observing the supersymmetric dynamics with photons. The time evolution operator is simulated approximately via Suzuki-Trotter expansion with considering the realization of the kinetic and potential terms separately. The former is realized through the diffraction nature of light and the later is implemented using phase plate. Additionally, we propose an interferometric approach which can be implemented perfectly using amplitude alternator to realize the non-unitary operator. The numerical results show that our scheme is universal and can be realized with current technologies., 7 pages

Intuition suggests that an object should carry all of its physical properties. However, a quantum object may not act in such a manner—it can temporarily leave some of its physical properties where it never appears. This phenomenon is known as the quantum Cheshire cat effect. It has been proposed that a quantum object can even permanently discard a physical property and obtain a new one it did not initially have. Here, we observe this effect experimentally by casting non-unitary imaginary-time evolution on a photonic cluster state to extract weak values, which reveals the counterintuitive phenomenon that two photons exchange their spins without classically meeting each other. A phenomenon presenting only in the quantum realm, our results are in stark contrast with the perception of inseparability between objects and properties, and shed new light on comprehension of the ontology of observables., The quantum Cheshire cat effect has already highlighted how, in the quantum realm, a physical property can be temporarily detached from an object. Here, the authors go a step further, experimentally demonstrating how a particle's spin can be permanently separated and exchanged with that of another particle.

Background Wnt-inducible signaling pathway protein 2 (WISP2) is a wnt1-induced signaling pathway protein 2. Although studies indicate that WISP2 may promote the development of various tumors, its role in ovarian cancer remains unclear. The objective of the current study was to analyze the effects of WISP2 on the proliferation and migration of ovarian cancer cells in vitro and in vivo. Results Immunohistochemistry and western blotting indicated that WISP2 was highly expressed in various ovarian cancer tissues and cell lines, but weakly expressed in normal ovary tissue. WISP2 deletion inhibited cell growth, clone formation, and migration of ovarian cancer cells while promoting cell apoptosis and affecting the cell cycle. This growth inhibitory effect caused by WISP2 loss is due to the inhibition of phosphorylated extracellular signal-related kinase (p-ERK)1/2, as well as CCAAT/enhancer-binding protein α (CEBPα) and CEPBβ. In addition, WISP2 deletion also activated the Yes-associated protein (YAP). Conclusion WISP2 deletion inhibits ovarian cancer cell proliferation by affecting ERK signaling pathways.

Mitogen-activated protein kinase (MAPK) cascades are key signalling pathways that regulate a wide variety of cellular processes, including proliferation, differentiation, apoptosis and stress responses. The MAPK pathway includes three main kinases, MAPK kinase kinase, MAPK kinase and MAPK, which activate and phosphorylate downstream proteins. The extracellular signal-regulated kinases ERK1 and ERK2 are evolutionarily conserved, ubiquitous serine-threonine kinases that regulate cellular signalling under both normal and pathological conditions. ERK expression is critical for development and their hyperactivation plays a major role in cancer development and progression. The Ras/Raf/MAPK (MEK)/ERK pathway is the most important signalling cascade among all MAPK signal transduction pathways, and plays a crucial role in the survival and development of tumour cells. The present review discusses recent studies on Ras and ERK pathway members. With respect to processes downstream of ERK activation, the role of ERK in tumour proliferation, invasion and metastasis is highlighted, and the role of the ERK/MAPK signalling pathway in tumour extracellular matrix degradation and tumour angiogenesis is emphasised.

Quantum processes of inherent dynamical nature, such as quantum walks, defy a description in terms of an equilibrium statistical physics ensemble. Until now, identifying the general principles behind the underlying unitary quantum dynamics has remained a key challenge. Here, we show and experimentally observe that split-step quantum walks admit a characterization in terms of a dynamical topological order parameter (DTOP). This integer-quantized DTOP measures, at a given time, the winding of the geometric phase accumulated by the wavefunction during a quantum walk. We observe distinct dynamical regimes in our experimentally realized quantum walks, and each regime can be attributed to a qualitatively different temporal behavior of the DTOP. Upon identifying an equivalent many-body problem, we reveal an intriguing connection between the nonanalytic changes of the DTOP in quantum walks and the occurrence of dynamical quantum phase transitions., Taking stock of a quantum walk A model describing the random walks of quantum particles has been developed by researchers in China and Germany. Classical phenomena such as molecules moving in gases or animals foraging for food can be described by random walks, where every step is chosen through processes like tossing a coin. For quantum particles, randomness arises from the transitions and entanglement of quantum states, but it is difficult to describe the emerging statistical patterns in these quantum walks. Chuan-Feng Li at the University of Science and Technology of China, Hefei, and co-workers used an experimental setup for observing the quantum walks of single photons. They found that the walks could be characterized by a so-called dynamical topological order parameter that describes the behavior of the particle’s wavefunction during the walk, thereby linking quantum effects to physical spatial measurements.

The authors experimentally elucidate the complete classification of quenched quantum walks. This paper extends the use of the dynamical Chern number, originally introduced in quenches of static systems, to periodically driven systems. These results show that the class of the quenches is related closely to the relevant quasi-equilibrium topological invariants.

Background and Aim Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic hepatitis, which leads to cirrhosis and hepatocellular carcinoma. However, it is difficult to identify subjects at high risk for NAFLD onset. This study aims to construct a model to predict the onset of NAFLD within 2 years in elderly adults. Methods This study included and followed 3378 initial NAFLD-free subjects aged 60 years or over for 2 years, which were randomly divided into a training set and a validation set. NAFLD was diagnosed on ultrasound. Clinical and laboratory data were recorded at baseline. A model was constructed in the training set to predict the onset of NAFLD and validated in the validation set. Results Body mass index, hemoglobin, fasting blood glucose, and triglycerides were identified as predictors for the onset of NAFLD. A risk score (R) was calculated by them. It classified the subjects into low-risk group (R ≤ −2.88), moderate-risk group (−2.88 −1.26). In the training set, 4.68% of the participants in the low-risk group, 11.59% of the participants in the moderate-risk group, and 31.02% of the participants in the high-risk group developed NAFLD. In the validation set, 5.84% of the participants in the low-risk group, 10.57% of the participants in the moderate-risk group, and 29.44% of the participants in the high-risk group developed NAFLD. Conclusions This study developed a model to predict the onset of NAFLD in elderly adults, which might provide indications for intervention to these subjects.

Background Whether or not EGFR mutation status detected by ddPCR in plasma predicts the effect of icotinib on patients with advanced lung adenocarcinoma was determined. Methods Plasma and matched tissue specimens from patients with advanced lung adenocarcinoma were collected prior to icotinib treatment. The ARMS method was used to detect EGFR mutation status in DNA extracted from tissue specimens, while the EGFR mutation status in ctDNA extracted from plasma specimens was determined by ddPCR. The therapeutic effects of icotinib were compared between patients with EGFR-activating mutations detected by ddPCR in ctDNA and ARMS in tissue DNA. Results EGFR mutation status was detected in 96 tissue and 100 plasma specimens. The sensitivity and positive predictive value of 19del detected in ctDNA by ddPCR was 70.97% (22/31) and 44.90% (22/49), respectively. The positive predictive value was 84.62% (22/26) and the sensitivity was 53.66% (22/41) for the L858R mutation. For the common sensitive EGFR mutations, ddPCR had a positive predictive value of 77.19% (44/57) and a sensitivity of 48.89% (44/90). Patients with sensitive EGFR mutations in ctDNA had objective response and disease control rates (DCR) similar to patients who had sensitive EGFR mutations in tissues detected by ARMS when treated with icotinib (57.14% vs. 51.51% and 92.86% vs. 90.91%, respectively). Conclusions Patients with sensitive EGFR mutations in plasma specimens detected with ddPCR had a higher ORR and DCR compared with patients with sensitive EGFR mutations in tissue detected with the ARMS method.

We report the first implementation of the von Neumann instantaneous measurements of nonlocal variables which becomes possible due to technological achievements in creating hyperentangled photons. Tests of reliability and of the nondemolition property of the measurements have been performed with high precision showing the suitability of the scheme as a basic ingredient of numerous quantum information protocols. The method allows to demonstrate for the first time with strong measurements a special feature of pre- and postselected quantum systems: the failure of the product rule. It has been verified experimentally that for a particular pre- and postselected pair of particles a single measurement on particle $A$ yields with certainty $\sigma_x^A=-1$, a single measurement on particle $B$ yields with certainty $\sigma_y^B=-1$, and a single nonlocal measurement on particles $A$ and $B$ yields with certainty $\sigma_x^A \sigma_y^B=-1$., Comment: 6 pages, 5 figures, to be published in PRL

Relativity theory severely restricts the ability to perform nonlocal measurements in quantum mechanics. Studying such nonlocal schemes may thus reveal insights regarding the relations between these two fundamental theories. Therefore, for the last several decades, nonlocal measurements have stimulated considerable interest. However, the experimental implementation of nonlocal measurements imposes profound restrictions due to the fact that the interaction Hamiltonian cannot contain, in general, nonlocal observables such as the product of local observables belonging to different particles at spacelike-separated regions. In this work, we experimentally realize a scheme for nonlocal measurements with the aid of probabilistic quantum erasure. We apply this scheme to the tasks of performing high accuracy nonlocal measurements of the parity, as well as measurements in the Bell basis, which do not necessitate classical communication between the parties. Unlike other techniques, the nonlocal measurement outcomes are available locally (upon successful postselection). The state reconstructed via performing quantum tomography on the system after the nonlocal measurement indicates the success of the scheme in retrieving nonlocal information while erasing any local data previously acquired by the parties. This measurement scheme allows realizing any controlled-controlled-gate with any coupling strength. Hence our results are expected to have conceptual and practical applications to quantum communication and quantum computation., Comment: 6 pages, 4 figures

Background The death-domain-associated protein (DAXX) was originally identified as a protein that binds to the transmembrane death receptor FAS and enhances both FAS-induced and transforming growth factor-β-dependent apoptosis. In a previous study, we found that nude mice injected with DAXX-overexpressing cells (ES-2-DAXX) accumulated large concentrations of first-generation ascites cells (I ascites cells). The role of DAXX in the development of ascites is unknown. The aim of this study was to analyze the effect of DAXX on proliferation and migration of ascites cells in ovarian cancer in vitro and in vivo. Methods Nude mice were housed in cages with a 14:10 h light:dark cycle; water and food were provided ad libitum. ES-2-DAXX cells (1×106) were injected intraperitoneally into athymic nude mice (8-week-old female mice). After 4 weeks, I ascites cells were collected. The I ascites cells were injected intraperitoneally into athymic nude mice (8-week-old female mice). After 4 weeks, II ascites cells were collected and cultured. Ascites cell survival, migration, and colony formation were measured using colony formation and cell growth assays. Immunofluorescent staining revealed the co-localization of DAXX and promyelocytic leukemia protein (PML) in ascites cell nuclei. Western blotting and immunohistochemistry showed that extracellular signal-related kinase (p-ERK) 1/2 and CEBP-β were highly expressed in tumor tissues formed by II ascites cells. Through immunoprecipitation, we also found that DAXX can interact with CEBP-β. Results DAXX enhanced ascites cell survival, migration, and colony formation. DAXX and PML nuclear foci dramatically increased in a passage-dependent manner in ascites cells, DAXX promoted the tumor growth of ascites cells in vivo, increased ascites cell proliferation in vivo, and enhanced ascites cell survival and migration by activating the ERK signalling pathway and integrating with CEBP-β. Conclusions DAXX can interact with CEBP-β. DAXX can induce ovarian cancer ascites formation by activating the ERK signal pathway and binding to CEBP-β.

N-Methyl-d-aspartate receptor (NMDAR) synaptic incorporation changes the number of NMDARs at synapses and is thus critical to various NMDAR-dependent brain functions. To date, the molecules involved in NMDAR trafficking and the underlying mechanisms are poorly understood. Here, we report that myosin IIb is an essential molecule in NMDAR synaptic incorporation during PKC- or θ burst stimulation-induced synaptic plasticity. Moreover, we demonstrate that myosin light chain kinase (MLCK)-dependent actin reorganization contributes to NMDAR trafficking. The findings from additional mutual occlusion experiments demonstrate that PKC and MLCK share a common signaling pathway in NMDAR-mediated synaptic regulation. Because myosin IIb is the primary substrate of MLCK and can regulate actin dynamics during synaptic plasticity, we propose that the MLCK- and myosin IIb-dependent regulation of actin dynamics is required for NMDAR trafficking during synaptic plasticity. This study provides important insights into a mechanical framework for understanding NMDAR trafficking associated with synaptic plasticity.

E3 ubiquitin ligase CRL4 complex activation requires cullin neddylation. MLN4924, a NEDD8-activating enzyme (NAE) inhibitor, reportedly blocked cullin neddylation and inactivated cullin (CUL)-RING E3 ligases (CRLs). Studies have shown that MLN4924 inhibits cell proliferation and survival. We examined the oncostatic and cytotoxic properties of MLN4924 in ovarian cancer. MLN4924 blocked human cancer cell proliferation in nude mice by inhibiting CpG binding protein CFP1 expression. Loss of CFP1 reduced cell growth, promoted apoptosis, and increased senescence. CFP1-dependent H3K4 trimethylation is necessary to maintain the expression of target genes in ovarian cancer cells. We identified bone marrow stromal cell antigen 2 (BST2) and noggin (NOG) as direct targets of CFP1. Their expression was selectively induced by CFP1 deletion. Furthermore, deletion of NOG and overexpression of BST2 prevented the growth-inhibitory effect of CFP1 loss. Our study further demonstrated that CRL4 inactivation reduced CFP1 transcription and trimethylation on lysine 4 of histone H3, which in turn inhibited cell proliferation and induced apoptosis. Therefore, CRL4 constitutes a druggable target in ovarian cancer. Citation Format: Liu-qing Yang, Han-yin Hu, Yao Han, Heng-Yan Zhu, Xiao-min Wang, Lei Ao, Ying Xu, Xuan Huang, Xuan Che, Li-Zhong Wang, Ya-Bo Jiang, Chun-wei Xu, Shu-Qun Cheng, Michal Heger, Wei-wei Pan. CpG binding protein promotes cell proliferation through H3K4 methylation in ovarian cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 130.

We experimentally demonstrate an alternative method for measuring nonlocal weak values in linear optics, avoiding the use of second-order interaction. The method is based on the concept of modular values. The paths of two photons, initialized in hyperentangled states, are adopted as the meter with the polarization acting as the system. The modular values are read out through the reconstructed final states of the meter. The weak value of nonlocal observables is given through its connection to the modular value. Comparing the weak values of local and nonlocal observables, we demonstrate the failure of product rules for an entangled system. Our results significantly simplify the task of measuring nonlocal weak values and will play an important role in the application of weak measurement.

How to reveal topological phases and their boundaries is an intriguing issue in various systems. Entanglement, which plays a fundamental role in quantum information, has been found profoundly related to topological phases. However, experimentally exploring this relation is precluded by the limited ability to obtain entanglement in many-body systems. In this work, we propose and experimentally demonstrate that the robustness of entanglement, quantified by the von Neumann entropy, can be used to reveal the topological phase with winding number W = 1 and topological phase with W = 0 in quantum walks. With the different robustness of entanglement against perturbations of a parameter, the phase boundaries between the distinct topological phases can be further determined. As a result, our work not only offers a new perspective for quantum walks but also exhibits the deep connection between entanglement and topological physics.

The Hippo pathway controls organ size and tissue homeostasis, and its dysregulation often contributes to tumorigenesis. Extensive studies have shown that the Hippo pathway inhibits cell proliferation, and survival in a cell-autonomous manner. We examined the function of the Hippo pathway kinases LATS1/2 (large tumor suppressor 1 and 2) in cancer cells. As expected, loss of LATS1/2 promotes cancer cell growth in most cell lines. Surprisingly, however, LATS1/2 deletion inhibits the growth of murine MC38 colon cancer cells, especially under detachment conditions. This growth inhibitory effect caused by LATS1/2 deletion is due to uncontrolled activation of Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), the key downstream transcriptional coactivators inhibited by LATS1/2. We identified Wnt inducible signaling pathway protein 2 (Wisp2) and coiled-coil domain containing 80 (Ccdc80) as direct targets of YAP/TAZ. Their expression is selectively induced by LATS1/2 deletion in MC38 cells. Furthermore, deletion of WISP2 and CCDC80 prevents the growth inhibitory effect of LATS1/2 loss in MC38 cells. Our study demonstrates that the function of LATS1/2 in cell growth is cell context dependent, suggesting that LATS1/2 inhibition can be a therapeutic approach for some cancer types.

We report the experimental measurement of the winding number in an unitary chiral quantum walk. Fundamentally, the spin-orbit coupling in discrete time quantum walks is implemented via birefringent crystal collinearly cut based on time-multiplexing scheme. Our protocol is compact and avoids extra loss, making it suitable for realizing genuine single-photon quantum walks at a large-scale. By adopting heralded single-photon as the walker and with a high time resolution technology in single-photon detection, we carry out a 50-step Hadamard discrete-time quantum walk with high fidelity up to 0.948$\pm$0.007. Particularly, we can reconstruct the complete wave-function of the walker that starts the walk in a single lattice site through local tomography of each site. Through a Fourier transform, the wave-function in quasi-momentum space can be obtained. With this ability, we propose and report a method to reconstruct the eigenvectors of the system Hamiltonian in quasi-momentum space and directly read out the winding numbers in different topological phases (trivial and non-trivial) in the presence of chiral symmetry. By introducing nonequivalent time-frames, we show that the whole topological phases in periodically driven system can also be characterized by two different winding numbers. Our method can also be extended to the high winding number situation., Comment: 26 pages, 8 figures

Entanglement generation in discrete time quantum walks is deemed to be another key property beyond the transport behaviors. The latter has been widely used in investigating the localization or topology in quantum walks. However, there are few experiments involving the former for the challenges in full reconstruction of the final wave function. Here, we report an experiment demonstrating the enhancement of the entanglement in quantum walks using dynamic disorder. Through reconstructing the local spinor state for each site, von Neumann entropy can be obtained and used to quantify the coin-position entanglement. We find that the enhanced entanglement in the dynamically disordered quantum walks is independent of the initial state, which is different from the entanglement generation in the Hadamard quantum walks. Our results are inspirational for achieving quantum computing based on quantum walks., Comment: 18 pages, 6 figures. arXiv admin note: text overlap with arXiv:1808.09278

OBJECTIVE: To investigate the possible causes of plagiocephaly in infants and the therapeutic effect of postural correction training on plagiocephaly. METHODS: A total of 101 infants who were diagnosed with plagiocephaly were enrolled. According to the age at diagnosis, these infants were divided into 1-4 month group (31 infants), 5-8 month group (40 infants), and 9-12 month group (30 infants). The possible causes of plagiocephaly were analyzed in three groups. The cranial vault asymmetry index (CVAI) before and after postural correction training was compared in three groups. RESULTS: Of the 101 infants, 89 (88.1%) had a sleeping posture in the supine position, and there was no significant difference in the percentage of infants with such posture between the three groups. Compared with the 5-8 month group and the 9-12 month group, the 1-4 month group had significantly higher rate of preterm birth, incidence rate of adverse perinatal factors, and incidence rate of congenital muscular torticollis. The three groups showed a significant decrease in CVAI 3 months after postural correction training (P < 0.001). Compared with the 5-8 month group and the 9-12 month group, the 1-4 month group had a significantly greater change in CVAI after postural correction training (P < 0.001). CONCLUSIONS: The sleeping posture in the supine position may be associated with the development of plagiocephaly. Adverse perinatal factors, preterm birth, and congenital muscular torticollis as possible causes of plagiocephaly are commonly seen in early infancy. Postural correction training has a significant effect in improving plagiocephaly, especially in early infancy.

Tet methylcytosine dioxygenases (TETs) catalyze the oxidative reactions of 5-methylcytosine to 5-hydroxymethylcytosine (5hmC). However, TET1 roles in ovarian cancer cell growth are unknown. Here, we show that ectopic expression of TET1 increased 5hmC levels, and inhibited proliferation and colony formation in ovarian cancer cell lines. Furthermore, in vitro and in vivo functional studies demonstrated that TET1 overexpression is necessary for the suppression of ovarian cancer growth, whereas depletion of TET1 expression had the opposite effect. Furthermore, the results of RNA-seq and qRT-PCR analyses identified a tumor suppressor, Ras association domain family member 5 (RASSF5), as the key downstream target of TET1. TET1 promotes RASSF5 expression by demethylating a CpG site within RASSF5 promoter. Up-regulated RASSF5 expression leads to the suppression of ovarian cancer cells growth. Additionally, we demonstrated that inhibition of CUL4-DDB1 ubiquitin ligase complex decrease 5hmC levels in ovarian cancer cells. These results provide new insights into the understanding of how ovarian cancers develop and grow, and identify TET1 as a key player in this process.

OBJECTIVE: To investigate the clinical effect of postural correction training and helmet therapy in the treatment of moderate-severe positional head deformity defined as asymmetric head shape in infants. METHODS: A total of 31 infants who were diagnosed with moderate-severe plagiocephaly and/or brachiocephaly were enrolled. According to the different treatment methods, the infants were divided into helmet therapy group with 11 infants and postural correction training group with 20 infants. The cranial vault asymmetry index (CVAI), cephalic ratio (CR), and head circumference growth were compared between the two groups before and after treatment. RESULTS: Compared with the postural correction training group, the helmet therapy group had significantly lower CVAI and CR after treatment. The helmet therapy group had significantly better improvements in CVAI and CR after treatment compared with the postural correction training group (CVAI difference: 6.0±1.9 vs 0.7±0.8, P=0.001; CR difference: 0.047±0.009 vs 0.008±0.005, P < 0.001). There was no significant difference in head circumference growth between the two groups (P=0.55). CONCLUSIONS: Helmet therapy has a significantly better effect in the treatment of moderate-severe positional head deformity than postural correction training in infants. Helmet therapy does not limit head circumference growth.

Poorly immunogenic tumor cells evade host immunity and grow even in the presence of an intact immune system, but the complex mechanisms regulating tumor immunogenicity have not been elucidated. Here, we discovered an unexpected role of the Hippo pathway in suppressing anti-tumor immunity. We demonstrate that, in three different murine syngeneic tumor models (B16, SCC7, and 4T1), loss of the Hippo pathway kinases LATS1/2 (large tumor suppressor 1 and 2) in tumor cells inhibits tumor growth. Tumor regression by LATS1/2 deletion requires adaptive immune responses, and LATS1/2 deficiency enhances tumor vaccine efficacy. Mechanistically, LATS1/2-null tumor cells secrete nucleic-acid-rich extracellular vesicles, which induce a typeI interferon response via the Toll-like receptors-MYD88/TRIF pathway. LATS1/2 deletion in tumors thus improves tumor immunogenicity, leading to tumor destruction by enhancing anti-tumor immune responses. Our observations uncover a key role of the Hippo pathway in modulating tumor immunogenicity and demonstrate a proof of concept for targeting LATS1/2 in cancer immunotherapy.

Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic hepatitis, which leads to cirrhosis and hepatocellular carcinoma. However, it is difficult to identify subjects at high risk for NAFLD onset. This study aims to construct a model to predict the onset of NAFLD within 2 years in elderly adults.This study included and followed 3378 initial NAFLD-free subjects aged 60 years or over for 2 years, which were randomly divided into a training set and a validation set. NAFLD was diagnosed on ultrasound. Clinical and laboratory data were recorded at baseline. A model was constructed in the training set to predict the onset of NAFLD and validated in the validation set.Body mass index, hemoglobin, fasting blood glucose, and triglycerides were identified as predictors for the onset of NAFLD. A risk score (R) was calculated by them. It classified the subjects into low-risk group (R ≤ -2.88), moderate-risk group (-2.88 R ≤ -1.26), and high-risk group (R -1.26). In the training set, 4.68% of the participants in the low-risk group, 11.59% of the participants in the moderate-risk group, and 31.02% of the participants in the high-risk group developed NAFLD. In the validation set, 5.84% of the participants in the low-risk group, 10.57% of the participants in the moderate-risk group, and 29.44% of the participants in the high-risk group developed NAFLD.This study developed a model to predict the onset of NAFLD in elderly adults, which might provide indications for intervention to these subjects.

Ubiquitin Fertility Insurance The female mammal's reproductive lifespan is determined by a pool of ovarian primordial follicles that are generated early in life. Yu et al. (p. 1518 ) found that in mice, the ubiquitin E3 ligase complex CRL4 is essential for oocyte survival within primordial follicles and for development after fertilization. CRL4 binds to and activates an adaptor protein that mediates ubiquitination, but if any component is deleted, the genes required for oocyte maintenance and early embryo development are silenced and the female mice become infertile.

Cullin-RING ubiquitin ligases (CRLs) are the largest family of E3 ligases and require cullin neddylation for their activation. The NEDD8-activating enzyme inhibitor MLN4924 reportedly blocked cullin neddylation and inactivated CRLs, which resulted in apoptosis induction and tumor suppression. However, CRL roles in ovarian cancer cell survival and the ovarian tumor repressing effects of MLN4924 are unknown. We show here that CRL4 components are highly expressed in human epithelial ovarian cancer tissues. MLN4924-induced DNA damage, cell cycle arrest, and apoptosis in ovarian cancer cells in a time- and dose-dependent manner. In addition, MLN4924 sensitized ovarian cancer cells to other chemotherapeutic drug treatments. Depletion of CRL4 components Roc1/2, Cul4a, and DDB1 had inhibitory effects on ovarian cancer cells similar to MLN4924 treatment, which suggested that CRL4 inhibition contributed to the chemotherapeutic effect of MLN4924 in ovarian cancers. We also investigated for key CRL4 substrate adaptors required for ovarian cancer cells. Depleting Vprbp/Dcaf1 did not significantly affect ovarian cancer cell growth, even though it was expressed by ovarian cancer tissues. However, depleting Cdt2/Dcaf2 mimicked the pharmacological effects of MLN4924 and caused the accumulation of its substrate, CDT1, both in vitro and in vivo. MLN4924-induced DNA damage and apoptosis were partially rescued by Cdt1 depletion, suggesting that CRL4(CDT2) repression and CDT1 accumulation were key biochemical events contributing to the genotoxic effects of MLN4924 in ovarian cancer cells. Taken together, these results indicate that CRL4(CDT2) is a potential drug target in ovarian cancers and that MLN4924 may be an effective anticancer agent for targeted ovarian cancer therapy.

Based on the relation between the wavelength shift of sensing FBG and the strain, a flow measuring device of the circular target binding Fiber Bragg Grating with the cantilever is designed and the mathematical model based on a circular target flow measurement system is established. Through the flow experiment, we can get the flow test result. The experimental data error analysis can be concluded to verify the feasibility and precision of the design.