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The use of tertiary amines as surrogates for secondary amines has prominent advantages in terms of stabilization and ease of handling. A Ni-catalyzed transamidation of N-acylsaccharins with tertiary aromatic amines is reported. By using tert-butyl hydroperoxide as the terminal oxidant, this reaction permits selective cleavage of the C(sp3)–N bonds of unsymmetrical tertiary aromatic amines depending on the sizes of the alkyl substituents.

Transition metal-catalyzed directed C–H activation has emerged as an increasingly powerful tool for the synthesis of important organic building blocks, organic materials and natural products. Despite the great advances in the past decades, the majority of C–H functionalization systems focus on aryl C–H activation. Given the wide presence of alkenes as substrates, olefinic C–H functionalization, which is a step-economic process, is highly desirable for the construction of functional olefins. Herein, we summarize the recent advances during 2015–2020 in the field of metal-catalyzed olefinic C–H functionalization. This review is organized according to the metal center of the catalyst, with an emphasis on the similarities and differences among different catalysts in olefinic C–H functionalization.

Comparisons of G protein-coupled receptor (GPCR) complexes with agonists and antagonists based on X-ray crystallography and cryo-electron microscopy structure determinations show differences in the width of the orthosteric ligand binding groove over the range from 0.3 to 2.9 Å. Here, we show that there are transient structure fluctuations with amplitudes up to at least 6 Å. The experiments were performed with the neurokinin 1 receptor (NK1R), a GPCR of class A that is involved in inflammation, pain, and cancer. We used 19F-NMR observation of aprepitant, which is an approved drug that targets NK1R for the treatment of chemotherapy-induced nausea and vomiting. Aprepitant includes a bis-trifluoromethyl-phenyl ring attached with a single bond to the core of the molecule; 19F-NMR revealed 180° flipping motions of this ring about this bond. In the picture emerging from the 19F-NMR data, the GPCR transmembrane helices undergo large-scale floating motions in the lipid bilayer. The functional implication is of extensive promiscuity of initial ligand binding, primarily determined by size and shape of the ligand, with subsequent selection by unique interactions between atom groups of the ligand and the GPCR within the binding groove. This second step ensures the wide range of different efficacies documented for GPCR-targeting drugs. The NK1R data also provide a rationale for the observation that diffracting GPCR crystals are obtained for complexes with only very few of the ligands from libraries of approved drugs and lead compounds that bind to the receptors.

Although the characteristics of the traveling 10-day waves (10DWs) above the middle stratosphere have been well explored, little research has been performed on the counterpart in the troposphere and lower stratosphere (TLS). In the present study, we use radiosonde observations and MERRA-2 data in 2020 to characterize traveling 10DWs in mid-latitudes in the TLS. Single-site observations in both hemispheres show that strong 10DW activities are always accompanied by strong eastward jets (10-13 km). MERRA-2 data indicates that in the troposphere the eastward-propagating modes with larger wavenumbers, i.e., E3, E4, E5 and E6 are dominant. While in the lower stratosphere the eastward- and westward-propagating modes with small zonal wavenumbers e.g., 1 and 2, are dominant. Further research on E3, E4, E5 and E6 modes in the troposphere of both hemispheres shows that all the wave activities are positively correlated to the background zonal wind. The refractive index squared reveal that a strong eastward jet is suitable for these four modes to propagate. However, just above the jet, the eastward wind decreases with altitude, and a thick evanescence region emerges above 15 km. E3, E4, E5 and E6 10DWs cannot propagate upward across the tropopause; as such this can explain why these four modes are weak or even indiscernible in the stratosphere and above. In the troposphere, E5 10DW at 32°S is the most dominant mode in 2020. A case study of the anomalously strong E5 10DW activity on May 12, 2020 indicates that the wave amplification resulted from the upward and equatorward transmission of wave energy flows. Moreover, the tropopause and equatorial region can prevent the propagations of wave energy flows of E5 10DW.

Acute kidney injury induced by cisplatin poses a serious health hazard to patients. Thus, this study was undertaken to elucidate key signaling pathways and hub genes relevant for therapeutic intervention involved in cisplatin-induced acute kidney injury(CI-AKI) by bioinformatics. We identified differentially expressed genes(DEGs) by R language on GSE106993 and GSE153625 datasets, downloaded from Gene Expression Omnibus (GEO). GO enrichment analysis and KEGG analysis were used to identify the main functions of common differential genes. The STRING database was used to construct protein-protein interaction (PPI) networks and hub genes were selected by Cytoscape. TransmiR v2.0 database and miRWalk2.0 database were used to construct transcription factor (TF)/microRNA (miRNA)/mRNA networks. Chinese herbal medicines targeting hub genes were screened by the ETMC database. 817 up-regulated genes and 769 down-regulated genes were obtained in CI-AKI model. Tumor necrosis factor(TNF) signaling pathway, P53 signaling, and metabolic signaling pathway are important pathways in CI-AKI. 8 hub genes were identified through PPI (Trp53、Egf、Stat3、Jun、Casp3、Cdh1、Ptgs2、Cat). We also constructed TF/microRNA/mRNA regulatory networks, including 2 TFs, 4 miRNAs and 214 mRNAs. The results of ETMC database analysis showed that Sang-Ye and Ban-Xia could be used for the treatment of CI-AKI. In this study, we identified 8 hub genes and 3 important signaling pathways in CI-AKI model by bioinformatics analysis, which provide targets for the treatment of CI-AKI. And the two Chinese herbal medicines obtained from our research, Sang-Ye and Ban-Xia, are expected to be used for the treatment of CI-AKI. Meanwhile, the TF/miRNA/mRNA networks we constructed are helpful to the further study of the mechanism of CI-AKI.

Machine learning models are widely deployed in production cloud to provide online inference services. Efficiently deploying inference services requires careful tuning of hardware and runtime configurations (e.g., GPU type, GPU memory, batch size), which can significantly improve the model serving performance and reduce cost. However, existing autoconfiguration approaches for general workloads, such as Bayesian optimization and white-box prediction, are inefficient in navigating the high-dimensional configuration space of model serving, incurring high sampling cost. In this paper, we present Morphling, a fast, near-optimal auto-configuration framework for cloud-native model serving. Morphling employs model-agnostic meta-learning to navigate the large configuration space. It trains a metamodel offline to capture the general performance trend under varying configurations. Morphling quickly adapts the metamodel to a new inference service by sampling a small number of configurations and uses it to find the optimal one. We have implemented Morphling as an auto-configuration service in Kubernetes, and evaluate its performance with popular CV and NLP models, as well as the production inference services in Alibaba. Compared with existing approaches, Morphling reduces the median search cost by 3x-22x, quickly converging to the optimal configuration by sampling only 30 candidates in a large search space consisting of 720 options.

Rhodium(III)-catalyzed annulation of 2-biphenylboronic acids with three classes of activated alkenes has been realized, leading to the synthesis of fused or bridged cyclic skeletons via transmetalation-initiated C-H activation. In the annulative coupling of 2-biphenylboronic acid with a CF3-substituted enone, the bulky cyclopentadienyl ligand (CptBu) in the catalyst proved effective to promote the reductive elimination process prior to protonolysis, affording the [4 + 2] annulated products instead of the simple 1,4-addition product. Seven-membered rings were obtained when disubstituted cyclopropenones were employed. Bridged cycles were isolated from the coupling of 2-biphenylboronic acid with benzoquinones as a result of 2-fold Michael additions. The substrate scopes were found to be broad with up to 99% yield under air-tolerant conditions.

Mature cystic teratoma is the most common ovarian germ cell tumor. The malignant transformation of ovarian mature cystic teratoma (MCT) is very rare, but the prognosis is poor. We present a case of ovarian mature cystic teratoma with human papillomavirus infection and malignant transformation into ovarian squamous cell carcinoma (SCC). The occurrence of this case may prove that high-risk human papillomavirus infection is a pathogenic factor inducing malignant transformation of mature cystic teratoma to SCC.A 38-year-old woman with a solid cystic mass of 8 cm on the right ovary, and human papillomavirus (HPV) test of her cervix showed HPV-16 infection.The transvaginal ultrasound was performed, and there was a cystic solid mass of 5.9 × 4.5 × 5.5 cm in the right adnexal area with unclear cystic fluid and rich blood flow signals in the capsule wall. HPV test of cervix showed HPV-16 infection. Diagnostic suspicion: cystic teratoma.The patient signed an laparoendoscopic surgery was performed to remove the right ovarian mass. Intraoperative pathology consultation revealed the malignant transformation of mature teratoma of the right ovary and the formation of squamous or adeno-SCC. We performed laparoscopic comprehensive surgical staging (hysterectomy, bilateral salpingo-oophorectomy, omentectomy, appendectomy, pelvic and para-aortic lymph node dissection) were made.The operation was successful and the postoperative recovery was smooth, was discharged 7 days after operation. Now the patient is recovering well and is continuing chemotherapy as planned.HR-HPV infection might be a causal factor for inducing malignant transformation of ovarian MCT to SCC, and the Jumping metastasis of lymph nodes may be the characteristic of SCC-MCT, but further verification is still needed.

Background: Myocarditis is an inflammatory heart disease caused by viral infections that can lead to heart failure, and occurs more often in men than women. Since animal studies have shown that myocarditis is influenced by sex hormones, we hypothesized that endocrine disruptors, which interfere with natural hormones, may play a role in the progression of the disease. The human population is exposed to the endocrine disruptor bisphenol A (BPA) from plastics, such as water bottles and plastic food containers. Methods: Male and female adult BALB/c mice were housed in plastic versus glass caging, or exposed to BPA in drinking water versus control water. Myocarditis was induced with coxsackievirus B3 on day 0, and the endpoints were assessed on day 10 post infection. Results: We found that male BALB/c mice that were exposed to plastic caging had increased myocarditis due to complement activation and elevated numbers of macrophages and neutrophils, whereas females had elevated mast cell activation and fibrosis. Conclusions: These findings show that housing mice in traditional plastic caging increases viral myocarditis in males and females, but using sex-specific immune mechanisms.

Network traffic classification is important for the management of network resource and the support quality of multimedia services. To realize the fine-grained classification of typical Internet video traffic, this paper studies and analyses the characteristics of video flow change in transmission process and the statistic characteristics of its main protocol data. According to different service models from the network services and the users’ demand of video quality, we propose two new sets of features for video traffic classification, including: downlink rate probability distribution model and main protocol data statistics. The experimental results show that the two sets of features can improve the performance of classification compared to existing methods.

Factor Xa (fXa) is a crucial player in various thromboembolic disorders. Inhibition of fXa can provide safe and effective antithrombotic effects. In this study, a series of anthranilamide compounds were designed by utilizing structure-based design strategies. Optimization at P1 and P4 groups led to the discovery of compound 16g: a highly potent, selective fXa inhibitor with pronounced in vitro anticoagulant activity. Moreover, 16g also displayed excellent in vivo antithrombotic activity in the rat venous thrombosis (VT) and arteriovenous shunt (AV-SHUNT) models. The bleeding risk evaluation showed that 16g had a safer profile than that of betrixaban at 1 mg/kg and 5 mg/kg dose. Additionally, 16g also exhibited satisfactory PK profiles. Eventually, 16g was selected to investigate its effect on hypoxia-reoxygenation- induced H9C2 cell viability. MTT results showed that H9C2 cell viability can be remarkably alleviated by 16g.

Background: The incidence of cervical cancer in young women is rising, and squamous cell carcinoma makes up a great percentage of the histological types. The presence of aggressive pathologic risk factors following patients’ primary surgery may warrant the use of adjuvant radiotherapy. It is important to weigh up the risks and benefits of using adjuvant radiotherapy for each young patient so as to maximize their prognosis while minimizing the treatment-related morbidity. Methods: A retrospective study was performed. It consisted of 97 patients under 35 years old who were diagnosed with cervical squamous cell carcinoma and underwent treatment at West China Second University Hospital between December 2009 and January 2014. Five-year follow-up, prognostic risks, long-term radiation toxicity, female sexual function, and quality of life were investigated. Results: Adjuvant radiotherapy did improve the prognosis of young patients with lymph node metastases. However, there were few significant differences in progress-free survival and overall survival for the young patients without lymph node metastases following adjuvant radiotherapy. Besides, young patients who took radiotherapy exhibited greater intestinal dysfunction, more severe lower extremities edema, greater sexual dysfunction, and worse long-term quality of life. Conclusion: Young patients with early-stage cervical squamous cell carcinoma without lymph node metastases who have undergone the primary surgery should be counseled in detail before the decision to use adjuvant radiotherapy can be made. The counseling should emphasize not only the benefit that local recurrence rates can be reduced, but also the risks that treatment-related side effects could increase and lower QoL could occur.

OBJECTIVE: To study vaginal delivery outcomes and neonatal prognosis and summarize the management of vaginal delivery during the COVID-19 pandemic. METHODS: A retrospective analysis of medical records and comparison of vaginal delivery outcomes between 10 pregnant women with clinical diagnosis of COVID-19 and 53 pregnant women without COVID-19 admitted to Zhongnan Hospital of Wuhan University between January 20 and March 2, 2020. Results of laboratory tests, imaging tests, and SARS-CoV-2 nucleic acid tests were also analyzed in neonates delivered by pregnant women with clinical diagnosis of COVID-19. RESULTS: There were no significant differences in gestational age, postpartum hemorrhage, and perineal resection rates between the two groups. There were no significant differences in birth weight of neonates and neonatal asphyxia rates between the two groups. Neonates delivered by pregnant women with clinical diagnosis of COVID-19 tested negative for SARS-CoV-2 infection. CONCLUSIONS: Under the premise of full evaluation of vaginal delivery conditions and strict protection measures, pregnant women with ordinary type COVID-19 can try vaginal delivery without exacerbation of COVID-19 and without increasing the risk of SARS-CoV-2 infection in neonates.

Mussels can strongly adhere to hydrophilic minerals in sea habitats by secreting adhesive proteins. The adhesion ability of these proteins is often attributed to the presence of Dopa derived from posttranslational modification of Tyr, whereas the contribution of structural feature is overlooked. It remains largely unknown how adhesive proteins overcome the surface-bound water layer to establish underwater adhesion. Here, we use molecular dynamics simulations to probe the conformations of adhesive protein Pvfp-5β and its salt-tolerant underwater adhesion on superhydrophilic mica. Dopa and positively charged basic residues form pairs, in this intrinsically disordered protein, and these residue pairs can lead to firm surface binding. Our simulations further suggest that the unmodified Tyr shows similar functions on surface adhesion by forming pairing structure with a positively charged residue. We confirm the presence of these residue pairs and verify the strong binding ability of unmodified proteins using nuclear magnetic resonance spectroscopy and lap shear tests.

BACKGROUND: Professional, standardized, and scientific management of the disinfection supply room is the prerequisite to ensure medical quality and improve the comprehensive strength of the hospital. This study aimed to evaluate the application of the defect management improvement mode of the Joint Commission International (JCI) standard in improving the cleaning and disinfection effect as well as the management quality of instruments in the central sterile supply department (CSSD). METHODS: From January 2020 to December 2020, 32 medical staff in the hospital CSSD were divided into control and observation groups according to the random number table method, with 16 staff members in each group. The control group adopted the standardized management mode and the observation group adopted the defect management improvement mode based on the JCI standard. During the management period, we compared the disinfection effect and incidence of adverse events of the instruments and articles in the CSSD of the two groups, and evaluated the work and satisfaction of both groups of subjects. Linear correlation analysis and multiple linear regression analysis were used to determine the influencing factors of satisfaction. RESULTS: During the standardized management, the instruments and articles were used 611 times in the control group and 602 times in the observation group. The cleaning qualified rate, infection awareness rate, standard implementation rate, hand hygiene implementation rate, theoretical knowledge score, and practical operation ability of the observation group were significantly higher than those of the control group (P

A new W–Cu potential has been established within the framework of the embedded-atom method (EAM) through the additional fitting of the structural energy differences between FCC and BCC structures of W and Cu. Based on this new potential, molecular dynamics simulations reveals that the lattice parameters of both BCC and FCC W–Cu solid solutions are bigger than those from the Vegard's law, and BCC and FCC W100-xCux solid solutions are thermodynamically more stable when 0 ≤ x ≤ 80 and 80

Copper-mediated 11C-cyanation reactions have enabled the synthesis of PET radiotracers from a range of readily available precursors and avoid the need to use more toxic Pd catalysts. In this work we adapt our recently developed 11C-cyanation of arylpinacolboronate (BPin) esters for the cGMP synthesis of [11C]LY2795050, a selective antagonist radiotracer for the kappa opioid receptor (KOR). [11C]LY2795050 was synthesized in 6 ± 1% noncorrected radiochemical yield (based on [11C]HCN, n = 3) using an automated synthesis module. Quality control testing confirmed the suitability of doses for preclinical and clinical PET imaging (radiochemical purity >99%; specific activity >900 mCi/μmol; residual Cu < 0.1 μg/mL). PET imaging was conducted in rodent and nonhuman primates, showing good brain uptake of [11C]LY2795050 and the expected distribution of KOR. Analogous imaging with [11C]carfentanil (a selective mu opioid receptor (MOR) radiotracer) revealed the anticipated regional differences in MOR and KOR distribution in the primate brain.

Spontaneous rupture of a vulvar hematoma during delivery is a relatively uncommon event and may cause excessive hemorrhage. Exact identification of anatomic structures and bleeding points is challenging. We herein present a case involving a pregnant woman at 39 weeks’ gestation with a large vulvar hematoma that spontaneously ruptured during the second stage of labor, likely due to rupture of varices in the vulva or vagina. It was difficult to accurately expose and suture the deep bleeding points. The estimated blood loss volume was 1591 mL, and the hemoglobin concentration dropped from 132 g/L before delivery to 84 g/L after delivery. To prevent hemorrhagic shock, bilateral internal iliac artery balloon occlusion was performed and proved to be an effective way to achieve hemostasis. Once hemostasis was established, ligation of the bleeding sites and suturing of all dead space were rapidly completed. Bilateral internal iliac artery balloon occlusion can be used as an effective treatment for excessive vaginal bleeding. The presence of varices or hemangiomas in the vulva or vagina should be carefully checked during antenatal care.

The paper proposes a set of features suitable for fine-grained traffic classification of network video, with data collected from real network. These features are parameters related to quality of experience (QoE), which reflects the user’s perception. The QoE value is calculated based on the ITU-T P.1201/Amd2 standard. Under this standard, each video flow can calculate corresponding QoE value and its probability of distribution. One innovative aspect of the paper is that the characteristics of QoE value and its probability distribution are extracted as the discriminating features which are suitable for video traffic classification. The extracted features of QoE distribution are typically mean, variance, maximum and minimum statistical characteristics, and the probability distribution of features can be obtained. Different from previous work, in our method, we obtain for the first time the discrete distribution of probability with five values, and use them directly as independent features to participate in feature selection and classification. The experimental results demonstrate that the proposed new features can significantly improve classification accuracy compared with an existing method.

In-vacuum undulators (IVU) [1–7] are used extensively at light source facilities, in particular at medium-energy storage rings, where these devices are the main sources of high-brightness hard X-ra...

A copper-mediated method for the transformation of diverse arylboron compounds and arylstannanes to aryl-[11C]-nitriles is reported. This method is operationally simple, uses commercially available reagents, and is compatible with a wide variety of substituted aryl- and heteroaryl substrates. This method is applied to the automated synthesis of high specific activity [11C]perampanel in 10% nondecay-corrected radiochemical yield (RCY).

Multimedia big data brings tremendous challenges as well as opportunities for multimedia applications/services. In this paper, we present a survey and tutorial for multimedia big data. After discussing the characteristics of multimedia big data such as human-centricity, multimodality, heterogeneity, unprecedented volume, and so on, this paper provides an overview of the state-of-the-art of multimedia big data, reviews the latest related technologies, and discusses the technical challenges. We conclude this paper with a discussion of open problems and future directions.

Cannabinoids are widely studied as therapeutic agents for the treatment of various diseases. Among them, THC and CBD are two important phytocannabinoids which have served as structural templates for the design of synthetic analogs. In this study, we designed and synthesized a variety of novel cannabinoids based on the structural backbones of THC and CBD using the carbon-silicon switch strategy. A dimethyl silyl group was introduced as the tail group and two series of novel compounds were designed and synthesized, which showed a wide range of binding affinity for CB1 and CB2 receptors. Among them, compound 15b was identified as a non-selective CB1 and CB2 agonist and 38b as a selective agonist for the CB2 receptor. Preliminary screening showed that both compounds have improved metabolic stability than their carbon analogs and good in vivo pharmacokinetic profiles. Furthermore, both 15b and 38b significantly alleviated the phenotype of experimental autoimmune encephalomyelitis (EAE) in mice.

Reflection-type photoplethysmography (PPG) pulse sensors are widely used in consumer markets to measure cardiovascular signals. Different from off-chip package solutions in which the light-emitting diode (LED) and photodetector (PD) are in separate chips, a GaN integrated optoelectronic chip with a novel ring structure is proposed to realize a PPG pulse sensor. The integrated optoelectronic chip consists of two multiple-quantum well (MQW) diodes. For higher sensitivities, the central and peripheral MQW diodes are suitable as the LED and PD, respectively. The results indicate that the integrated optoelectronic chip based on a blue LED epitaxial wafer is more suitable for the integrated PPG sensor based on device performance. Moreover, the amplitude of the PPG pulse signal collected from fingertips is higher than that from a wrist. The feasibility of the reflection-type PPG pulse sensor based on a GaN integrated optoelectronic chip is fully verified with the advantages of smaller sizes and lower costs.

Glycyrrhetic acid (GA), the main hydrolysate of glycyrrhizic acid extracted from the roots of the Chinese herb Glycyrrhiza glabra, was reported to be accumulated in hepatocytes due to the extensive distribution of GA receptors in liver. A series of hepatocyte-specific derivatives on the basis of anetholtrithione and glycyrrhizic were designed and synthesized. The potential beneficial effect was evaluated in carbon tetrachloride (CCl4)-induced liver injury model. In addition, the hepatoprotective activity of these derivatives was assessed by measuring levels of serum marker enzymes, including serum glutamate oxaloacetate transaminase (GOT), serum glutamate pyruvate transaminase (GPT), alkaline phosphatase (AKP), lactate dehydrogenase (LDH) and the ratio of GSH to GSSG. Gratifyingly, compounds 5a-c (100mg/kg, p.o.) markedly prevented CCl4-induced elevation of levels of serum GPT, GOT. A comparative histopathological study of liver exhibited almost a normal liver lobular architecture and cell structure of the livers, as compared to CCl4-treated group. These findings were confirmed with the histopathological observations, where hepatocyte-specific glycyrrhetic acid derivatives 5a-c were capable of reversing the toxic effects of CCl4 on hepatocytes.

Programmed cell death protein 1 (PD-1) acts on PD-1 ligands (PD-L1 and PD-L2) to suppress activation of cytotoxic T lymphocytes. Interleukin-17 (IL-17) and tumor necrosis factor-α (TNF-α) are co-expressed by T helper 17 (TH17) cells in many tumors. The purpose of this study was to test if IL-17 and TNF-α may synergistically induce PD-L1 expression in human prostate cancer LNCaP and human colon cancer HCT116 cell lines. We found that IL-17 did not induce PD-L1 mRNA expression, but up-regulated PD-L1 protein expression in HCT116 and LNCaP cells. TNF-α induced PD-L1 mRNA and protein expression in both cell lines. Neither IL-17 nor TNF-α induced PD-L2 mRNA or protein expression. IL-17 and TNF-α acted individually rather than cooperatively in induction of PD-L1 expression. IL-17 and/or TNF-α activated AKT, nuclear factor-κB (NF-κB), and extracellular signal-regulated kinases 1/2 (ERK1/2) signaling pathways in HCT116 cells, whereas only NF-κB signaling was activated in LNCaP cells. NF-κB inhibitor could diminish PD-L1 protein expression induced by IL-17 and/or TNF-α in both HCT116 and LNCaP cell lines. ERK1/2 inhibitor could also reduce PD-L1 protein expression induced by IL-17 and/or TNF-α in HCT116 cells, while AKT inhibitor could abolish PD-L1 protein expression induced by IL-17 and/or TNF-α in LNCaP cells. These results suggest that IL-17 and TNF-α act individually rather than cooperatively through activation of NF-κB and ERK1/2 signaling to up-regulate PD-L1 expression in HCT116 cells, while the two inflammatory cytokines act through activation of NF-κB signaling, in the presence of AKT activity, to up-regulate PD-L1 expression in LNCaP cells.

BRD4 is an attractive target for antitumor due to its important role in regulation of gene transcription. In this paper, we synthesized a series of 7-methylimidazo[1,5- a ]pyrazin-8(7 H )-one derivatives as potent BRD4 inhibitors and evaluated their BRD4 inhibitory activities in vitro and anti-proliferation effects on tumor cells. Gratifyingly, compound 10j exhibited robust potency of BRD4(1) and BRD4(2) inhibition with IC 50 values of 130 and 76 nM respectively. Docking studies were performed to explain the structure-activity relationship. Furthermore, compound 10j potently inhibited cell proliferation in BRD4-sensitive cell lines HL-60 and MV4-11 with IC 50 value of 0.57 and 0.18 μM respectively. Activity on BRD4-independent K562 cell was weaker than on BRD4-sensitive lines. Overall, these results suggest that compound 10j is a potential BRD4 inhibitor deserving further investigation for cancer treatment.

Let D be a Scott-domain and [ D → c D ] (resp., [ D → s D ] ) its conditionally multiplicative (CM for short) (resp., stable) function space. Zhang (1996) [19] mentioned that if [ D → c D ] is bounded complete, D should be distributive. In the first part of this paper, we prove that if [ D → c D ] or [ D → s D ] is bounded complete, then D is distributive, which confirms that his conjecture is true. Amadio (1991) [3] and Curien (1998) [4] raised the question of whether the category of stable bifinite domains (SB for short) in sense of Amadio–Droste is the largest Cartesian closed full subcategory of the category of ω-algebraic meet-cpos with CM functions (ω-SAM for short). In the second part of this paper, we prove that for any ω-algebraic meet-cpo D and certain non-distributive finite poset M ˜ , if [ D → c M ˜ ] , [ [ D → c M ˜ ] → c [ D → c M ˜ ] ] and [ [ [ D → c M ˜ ] → c M ˜ ] → c [ [ D → c M ˜ ] → c M ˜ ] ] are ω-algebraic, then we have that (1) D is finitary; (2) if D is not stable bifinite, then [ [ D → c M ˜ ] → c [ D → c M ˜ ] ] is not finitary. So, the category SB is a maximal Cartesian closed full subcategory of ω-SAM, which gives a partial solution to the problem posed by Amadio and Curien.

ObjectiveEstrogen is a well-known oncogenic driver in endometrial (ECs) and breast cancers (BCs). Programmed cell death protein 1 (PD-1) and its ligands PD-1 Ligand 1 (PD-L1) and PD-L2 have been shown to mediate immune evasion of the tumor cells. The purpose of the present study was to assess the effects of estrogen on PD-L1 and PD-L2 expression in EC and BC cell lines.Methods17β-Estradiol (E2)–induced expression of PD-L1 and PD-L2 and possible signaling pathway were investigated in EC and BC cells. Coculture of T cells and cancer cells with E2 stimulation was performed to assess the functions of T cells.ResultsWe found that E2 increased expression of PD-L1, but not PD-L2, protein via activation of phosphoinositide 3-kinase (PI3K)/Akt pathway in Ishikawa and Michigan Cancer Foundation-7 (MCF-7) cells. Phosphoinositide 3-kinase and Akt inhibitors could block E2’s effects. 17β-Estradiol did not increase PD-L1 mRNA transcription, but stabilized PD-L1 mRNA. 17β-Estradiol’s effects were only observed in estrogen receptor α (ERα)–positive Ishikawa and MCF-7 cells, but not in ERα-negative MDA-MB-231 cells. Coculture of Ishikawa or MCF-7 cells with T cells inhibited expression of interferon-γ and interleukin-2 and increased BCL-2-interacting mediator of cell death expression in the presence of E2.ConclusionsThis study provides the first evidence that estrogen upregulates PD-L1 protein expression in ERα-positive EC and BC cells to suppress immune functions of T cells in the tumor microenvironment, demonstrating a new mechanism of how estrogen drives cancer progression.

Coagulation factor Xa (fXa) is a particularly attractive target for the development of effective and safe anticoagulants. In this study, novel 2,3-dihydroquinazolin-4(1H)-one derivatives were designed as potential fXa inhibitors based on anthranilamide structure which has been reported in our previous research. The experimental data showed that most of the designed compounds exhibited significant in vitro potency against fXa. Among them, compound 8e displayed the strongest potency against fXa with the IC50 value of 21 nM and highly selectivity versus thrombin (IC50 = 67 μM) and excellent in vitro antithrombotic activity with its 2 × PT value of 1.2 μM and 2 × aPTT value of 0.6 μM. In addition, 8e also displayed excellent in vivo antithrombotic activity in the rat arteriovenous shunt (AV-SHUNT) model. The bleeding risk evaluation showed that 8e had a similar safety profile as that of betrixaban. All results demonstrated that compound 8e could be considered as a potential fXa inhibitor for the prevention and treatment of thromboembolic diseases.

Accumulating evidence demonstrates that long noncoding RNAs (lncRNAs) may be involved in the regulation of cancer biology. PVT1, which is overexpressed in tumor samples, acts as an oncogenic promoter in several kinds of cancers, including ovarian cancer. However, the mechanisms of its regulation of malignant behaviors in ovarian cancer remain largely unknown. In this study, the expression of PVT1 in several ovarian cancer cell lines was analyzed by qRT-PCR. The effect of PVT1 on malignant behaviors, including cell proliferation, migration and invasion, was analyzed. The posttranscriptional regulation of FOXM1 by PVT1 was analyzed by western blotting. The results illustrated that PVT1 acted as a sponge and bound miR-370 on two binding sites. The expression of PVT1 positively regulated malignant behaviors in ovarian cancer cells, including cell proliferation, migration and invasion, which could be reversed by the introduction of miR-370 mimics. Sponged miR-370 failed to posttranscriptionally regulate FOXM1, which resulted in the promotion of malignant behavior. PVT1 was also found to bind to FOXM1 directly and stabilize the FOXM1 protein. The promoting effect of PVT1 on malignant behaviors and chemoresistance to cisplatin could be reversed by knockdown of FOXM1 and introduction of miR-370 mimics. Together, these results suggest that lncRNA PVT1 promotes malignant behavior and induces chemoresistance in ovarian cancer by epigenetic and posttranscriptional regulation of FOXM1.

Introduction/Background Endometriod cancer (EC) is identified as one of the estrogen-dependent malignancies in women worldwide. Estrogen-stimulated cellular proliferation remains the conceptual underpinning of estrogen receptor(ER) dependent mechanism in EC development and progression. The immune checkpoint PD-1/PD-L1 plays a major role in immune suppression within the tumor microenvironment. The aim of this study is to evaluate the expression and prognostic function of PD-1 and PD-L1 in EC and to assess the effects of 17β-estradiol (E2) on PD-L1 expression in estrogen-dependent cancer. Methodology Paraffin sections of EC patients were used for immunohistochemical (IHC) staining using PD-1 and PD-L1 antibodies. All patients were selected for follow-up and prognostic analysis. Real-time quantitative PCR (q-PCR) and Western blot were performed to detect the mRNA and protein levels of PD-L1 after E2 treatment in estrogen-dependent cancer cells. The mechanism was investigated through co-immunoprecipitation, degradation analysis, sucrose gradient centrifugation and polysome analysis. Results PD-L1 is highly expressed in epithelium of endometrioid adenocarcinoma, accompanying with more PD-1 positive infiltrating lymphocytes in stroma. Highly expressed PD-L1, associated with advanced stage and high-grade differentiation, shortens the disease-free survival (DFS) and affects prognosis of patients with endometrioid adenocarcinoma. High level and unopposed E2 in tumor microenvironment leads to specific combination of membrane ERα and PI3K p85α regulatory subunit, recruiting PIP3 to phosphorylate No. 473 serine of Akt and forming the active type p-Akt. Activation of Akt can stabilize PD-L1 mRNA and increase PD-L1 translation efficiency. Co-culture results shows that up-regulating PD-L1 expression and activating PD-1/PD-L1 pathway leads to inhibition of T cell activity. Conclusion Our results demonstrate a new role of estrogen in regulation of anti-cancer immunity, implying PD-L1 as a potential therapeutic target or an outcome parameter in anti-estrogen treatment of EC and estrogen- dependent cancer. Disclosure Nothing to disclose.

Clustering analysis is the core technology of data mining. However, massive data analysis makes it difficult for traditional clustering algorithms to have better clustering effects. At present, a more effective way to solve such problems is to detect the cluster boundary by means of the boundary point detection algorithm, and then combine it with the clustering algorithm. In this paper, we propose a clustering boundary points detection algorithm based on data representation. It does not need to understand the dimension and the meaning of data. It is only necessary to construct the expression matrix W through a specific algorithm and then we can recognize the boundary points of the data set through computing the number of zero and negative components of W, which helps us capture the inner structure of data about clustered data. Meanwhile, our algorithm overcomes the dimensional disaster of traditional algorithms on high-dimensional data sets. In addition, the algorithm has a high recall rate and accuracy on both synthetic data sets and real data sets.

A bottleneck for developing CO-based therapeutics is the lack of a safe and controllable delivery form. Herein, we describe efforts toward organic CO prodrugs with dual-responsive endogenous triggers. One representative CO prodrug showed significant anti-inflammatory effects both in vitro and in a LPS-simulated systemic inflammation model. These results firmly establish such CO prodrugs as either research tools or candidate compounds for the treatment of systemic inflammation or inflammation related organ injuries.