Synthesis and biological evaluation of 2,5-diaryl-1,3,4-oxadiazole derivatives as novel Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) inhibitors.

The Src homology-2 domain containing-protein tyrosine phosphatase-2 (SHP2) is a convergent node for oncogenic cell-signaling cascades including the PD-L1/PD-1 pathway. As an oncoprotein as well as a potential immunomodulator, SHP2 has now emerged as an attractive target for novel anti-cancer agents. Although significant progress has been made in identifying chemotypes of SHP2 inhibitors, these specific compounds might not be clinically useful to inhibit frequently encountered mutated SHP2 variants. Consequently, it is highly desirable to develop chemically different SHP2 inhibitors sensitive to SHP2 mutants. This work developed a new type of SHP2 inhibitors with 2,5-diaryl-1,3,4-oxadiazole scaffold. The representative compound 6l exhibited SHP2 inhibitory activity with IC50 of 2.73 ± 0.20 µM, showed about 1.56-fold, 5.26-fold, and 7.36-fold selectivity for SHP2 over SHP1, PTP1B and TCPTP respectively. Further investigations confirmed that 6l behaved as mixed-type inhibitor sensitive to leukemia cell TF-1 and inhibited SHP2 mediated cell signaling and proliferation. Molecular dynamics simulation provided more detailed information on the binding modes of compounds and SHP2 protein. These preliminary results could provide a possible opportunity for the development of novel SHP2 inhibitors sensitive to SHP2 mutants with optimal potency and improved pharmacological properties.

Luminescent Thermochromism and White-Light Emission of a 3D [Ag4Br6] Cluster-Based Coordination Framework with Both Adamantane-like Node and Linker.

Herein, we report a dia-type metal-organic hybrid network based on the [Ag4Br6] clusters and hexamethylenetetramine molecules wherein both the inorganic nodes and organic linkers feature adamantane-like geometry with a Td symmetry. The silver bromine complex presents a dual emission and exhibits an interesting luminescent thermochromism behavior. Remarkably, white-light emission can be readily realized through variation of the temperature. In addition, the title compound is expected to be competent as a luminescent thermometer for temperature identification.

Assessment of clinical efficacy of traditional Chinese medicine for the management of primary dysmenorrhea in the UK: A protocol of systematic review.

BACKGROUND: This study aims to appraise the clinical efficacy of traditional Chinese medicine (TCM) for the management of patients with primary dysmenorrhea (PD) in the UK. METHODS: We will comprehensively search electronic databases (Cochrane Library, PUBMED/MEDLINE, EMBASE, PsycINFO, AMED, Web of Science, and CNKI) and additional resources for original articles on randomized controlled trials published in English, Chinese, German, Spanish, Korean and Japanese. Outcomes will be the pain intensity, pain duration, menstrual cramps, amount of bleeding, and severity of dysmenorrhea symptoms, quality of life, and adverse events. Two authors will independently check all citations, extract data, and assess study quality. All potential conflicts will be solved through discussion by consulting another experienced author. A narrative synthesis will summarize the characteristics and findings of eligible trials. If it is possible, we will also pool the data and carry out meta-analysis. RESULTS: The available evidence of the clinical efficacy of TCM for the treatment of PD in UK will be assessed through outcome measurements. CONCLUSION: The findings of this study will determine whether or not TCM is effective and safe for the treatment of PD in UK. OSF REGISTRATION NUMBER:: osf.io/jyc95.

Knockdown of GAS5 Inhibits Atherosclerosis Progression via Reducing EZH2-Mediated ABCA1 Transcription in ApoE-/- Mice.

Atherosclerosis is a disorder occurring in the large arteries and the primary cause of heart diseases. Accumulating evidence has implicated long non-coding RNAs (lncRNAs) in atherosclerosis. This study aims to clarify the potential effects of lncRNA growth arrest-specific 5 (GAS5) on cholesterol reverse-transport and intracellular lipid accumulation in atherosclerosis. GAS5 was mainly localized in the nucleus and highly expressed in the human monocytic leukemia cell line (THP-1) macrophage-derived foam cells in coronary heart disease. Overexpressed GAS5 increased THP-1 macrophage lipid accumulation. Of note, GAS5 can inhibit the expression of ATP-binding cassette transporter A1 (ABCA1) by binding to enhancer of zeste homolog 2 (EZH2). Overexpression of EZH2 reduced cholesterol efflux and ABCA1 expression. EZH2 promoted triple methylation of lysine 27 (H3K27) in the ABCA1 promoter region. Subjected to overexpressed GAS5, overexpressed EZH2, or downregulated ABCA1, the Apolipoprotein E (ApoE)-/- mice with atherosclerosis showed increased total cholesterol (TC), free cholesterol (FC), cholesterol ester (CE), low-density lipoprotein (LDL) levels, aortic plaque, and lipid accumulation, accompanied by reduced high-density lipoprotein (HDL) level and cholesterol outflow. Altogether, knockdown of GAS5 can potentially promote reverse-transportation of cholesterol and inhibit intracellular lipid accumulation, ultimately preventing the progression of atherosclerosis via reducing EZH2-mediated transcriptional inhibition of ABCA1 by histone methylation.

Efficacy of tolvaptan for chronic heart failure: Study protocol for a systematic review of randomized controlled trial.

BACKGROUND: The protocol of this study will be proposed for systematic evaluation of the efficacy and safety of tolvaptan in the treatment of chronic heart failure (CHF). METHODS: We will retrieve the following electronic databases for randomized controlled trials assessing the efficacy of tolvaptan in patients with CHF: PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, Scopus, Chinese Biomedical Literature Database, China National Knowledge Infrastructure, VIP Information, and Wanfang Data. Each database will be retrieved from inception to February 1, 2019 without any limitations. The entire process of study selection, data extraction, and methodological quality evaluation will be conducted by 2 independent authors. RESULTS: The protocol of this proposed study will compare the efficacy and safety of tolvaptan in the treatment of patients with CHF. The outcomes will include all-cause mortality, change in body weight, urine output, change in serum sodium; and incidence of all adverse events. CONCLUSION: The findings of this proposed study will summarize the current evidence of tolvaptan for CHF. ETHICS AND DISSEMINATION: All data used in this systematic review will be collected from the previous published trials. Thus, no research ethics approval is needed for this study. The findings of this study will be published at a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: PROSPERO CRD42019120818.

Amiodarone and acupuncture for cardiac arrhythmia: Study protocol for a systematic review.

BACKGROUND: Amiodarone and acupuncture (AA) are commonly used to treat cardiac arrhythmia (CA). The objective of this systematic review is to assess the efficacy and safety of AA for patients with CA. METHODS: Randomized controlled trials (RCTs) of AA for CC will be searched from 9 databases including PubMed, EMBASE, Cochrane Library, Web of Science, Scopus, Chinese Biomedical Literature Database, China National Knowledge Infrastructure, VIP Information, and Wanfang Data from inception to February 1, 2019 without any limitations. Two reviewers will independently screen the relevant papers, extract data, and evaluate the risk of bias for each included study. RevMan 5.3 software will be used for meta-analysis. The primary outcome includes arrhythmic episodes (including time and frequency domain parameters). The secondary outcomes consist of health-related quality of life, oxygen saturation, and safety. RESULTS: The protocol of this proposed study will provide evidence to judge whether AA is an effective treatment for patients with CA. CONCLUSION: The findings of this proposed study will summarize the up-to-date evidence of AA for CA. PROSPERO REGISTRATION NUMBER: PROSPERO CRD42019120962.

Quantum man-in-the-middle attack on the calibration process of quantum key distribution.

Quantum key distribution (QKD) protocol has been proved to provide unconditionally secure key between two remote legitimate users in theory. Key distribution signals are transmitted in a quantum channel which is established by the calibration process to meet the requirement of high count rate and low error rate. All QKD security proofs implicitly assume that the quantum channel has been established securely. However, the eavesdropper may attack the calibration process to break the security assumption of QKD and provide precondition to steal information about the final key successfully. In this paper, we reveal the security risk of the calibration process of a passive-basis-choice BB84 QKD system by launching a quantum man-in-the-middle attack which intercepts all calibration signals and resends faked ones. Large temporal bit-dependent or basis-dependent detector efficiency mismatch can be induced. Then we propose a basis-dependent detector efficiency mismatch (BEM) based faked states attack on a single photon BB84 QKD to stress the threat of BEM. Moreover, the security of single photon QKD systems with BEM is studied simply and intuitively. Two effective countermeasures are suggested to remove the general security risk of the calibration process.

The design of an optical triode.

Under the action of pump light, a conventional photonic crystal can be turned into a functional photonic crystal. In the paper, we have designed an optical triode with a one-dimensional functional photonic crystal, and analyzed the effect of period number, medium thickness, refractive index, incident angle, the irradiation frequency and the intensity of the pump light on the optical triode magnification. We obtain some valuable results, which shall help to optimize the design of optical triodes.

[CD8+ cell noncytotoxic antiviral response (CNAR) to HIV in nosocomial HIV-infected individuals].

OBJECTIVE: To study the CD8+ cell noncytotoxic antiviral response (CNAR) to HIV in nosocomial HIV infected individuals, and reveal the relationship between the CNAR and CD4+ cell count. METHOD: CD8+ cells from HIV-1 sero-positive individuals were separated by immunomagnetic beads and mixed with CD4+ cells at different CD8 CD4 cell input ratios (2:1, 1:1, 0.5:1 and 0.25:1). Reverse transcriptase (RT) activity of cocultured supernatant was tested and compared with negative control and the suppression rate of HIV-1 replication was measured. RESULT: The average CD8:CD4 cell input ratios to reach 80% suppression of HIV replication in the group with CD4 < 300/microl and CD4 > 300/microl were 2.4:1 and 1.3:1, respectively (P < 0.05). CONCLUSION: CNAR activity in HIV infected individuals is associated with CD4+ cell count. The ability to suppress HIV replication in subjects with CD4 > 300 is stronger than those with CD4 < 300.

[An ambispective cohort study of the natural history of HIV infection among former unsafe commercial blood and plasma donors].

OBJECTIVE: Discussing the natural history and the influencing factors of HIV infection among former commercial blood and plasma donors engaged in unsafe blood donation practices in China. METHODS: Using ambispective cohort study, with data obtained from ten counties (districts) from six provinces in the National AIDS Control Demonstration Area. HIV/AIDS cases were found and confirmed prior to July 24, 2006 being former commercial blood. Plasma donors were selected and data regarding infection, incidence, death, and influencing factors was collected. Analysis was performed using SPSS 12.0 statistical analysis software. RESULTS: (1) In 7551 cases of HIV infection, there were 6533 typical progressors (86.52%, 4757 cases of AIDS), 108 rapid progressors (1.43%), 910 long-term non-progressors (12.05%) with 4865 cases progressed to AIDS (64.43%). The median incubation period for HIV progression to AIDS was nine years (95% CI:8.96-9.04). (2) According to data, from a total of 1157 AIDS cases without ARV therapy (23.78% of total AIDS cases), there were 283 confirmed AIDS-related deaths, of which the median survival time was 6 months (95% CI:4-7) and the two and three year fatality rates were 95% and 99%, respectively. (3) The duration of HIV incubation period was irrespective to gender and age at the time of HIV infection (P > 0.05). Length of survival for untreated AIDS showed correlation to gender (P < 0.05) but no correlation with culture, marital status or age at the time of diagnosis of AIDS (P > 0.05). CONCLUSION: Compared with the UNAIDS theory regarding slow disease progressors among adults, our study showed a longer AIDS incubation period and shorter outlook for untreated survival, but a similar incubation period for other routes of HIV infection.

The impacts of current antiretroviral therapy regimens on Chinese AIDS patients and their implications for HIV-1 drug resistance mutation.

This study sought to investigate the impacts of the antiretroviral (ARV) therapy regimens currently used in Chinese HIV-1-infected individuals. Seven hundred eighteen ARV-treated and treatment-naive HIV-1-infected individuals living in seven provinces were enrolled in 2005 by a multistage sampling approach according to a national cross-sectional survey program on HIV-1 drug resistance. All patients were investigated clinically, and CD4+ T cell counts and HIV-1 viral loads were measured while genotyping for drug resistance was determined by a home brew nested PCR. Viral inhibition in ARV-treated individuals was higher than that in ARV treatment-naive individuals. The overall prevalence of drug-resistant mutations was 37.8%. Higher frequencies of mutations in ARV-treated and drug withdrawal groups were found than in the ARV treatment-naive group (P<0.01). Of the four regimens currently used, the D4T/3TC/NVP regimen showed a higher-level viral inhibition. No statistical significance was found among the four regimens in drug-resistant mutations. The rate of resistance-associated mutations to non-nucleotide reverse transcriptase inhibitors (NNRTIs) was higher than that to nucleotide reverse transcriptase inhibitors (NRTIs) (P<0.01). The most common mutations conferring resistance to NNRTIs were K103N, Y181C and G190A, representing 56.5, 30.4 and 14.5%, respectively. Furthermore, higher viral inhibition and a lower rate of drug-resistant mutations were achieved in the good compliance group. This study revealed an efficient viral inhibition achieved with the current first-line regimens in China. Most of these regimens could rapidly result in emergence of drug-resistant mutations, suggesting that a second-line ARV therapy is urgently needed and that the compliance with treatment must be emphasized during long-term treatment.