Effects and safety of Tanreqing injection on viral pneumonia: A protocol for systematic review and meta-analysis.

BACKGROUND: Influenza-related viral pneumonia is a severe threat to human health, which has caused high morbidity and mortality each year. The objective of this study was to assess the efficacy and safety of Tanreqing Injection therapy in patients with viral pneumonia. MATERIALS AND METHODS: This protocol established in this study has been reported following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols. Web of Science, PubMed, EMBASE and the Cochrane Library were searched for clinical randomized trials in cases with viral pneumonia until 1st of July 2020. We will use a combination of Medical Subject Heading and free-text terms with various synonyms to search based on the Eligibility criteria. Two investigators independently reviewed the included studies and extracted relevant data. The relative risk (RR) and 95% confidence intervals (CIs) of were used as effect estimate. I-square (I) test, substantial heterogeneity, sensitivity analysis and publication bias assessment will be performed accordingly. Stata 14.0 and Review Manger 5.3 are used for meta-analysis and systematic review. RESULTS: The results will be published in a peer-reviewed journal. CONCLUSION: The results of this review will be widely disseminated through peer-reviewed publications and conference presentations. This evidence may also provide helpful evidence of whether Tanreqing Injection therapy was efficient and safe in patients with viral pneumonia. PROSPERO REGISTRATION NUMBER: CRD42020164164.

Synthesis of tricyclic benzimidazole-iminosugars as potential glycosidase inhibitors via a Mitsunobu reaction.

A series of tricyclic benzimidazole-iminosugars 1(a-f) and 2(a-f) were synthesized and evaluated for their their inhibitory activities against five glycosidases. The synthesis initiated from the benzyl protected sugar (aldehyde) 5 that reacted with 1,2-diaminobenzene to afford aldo-benzimidazole 6 by the iodine-induced oxidative condensation. Then, tricyclic compound 7 was obtained in high yields of 73%-87% by the key Mitsunobu reaction through intramolecular cyclization of the unprotected OH and the NH in 6. After removal of the benzyl group in CF3SO3H, the target tricyclic benzimidazole-iminosugars 1 and 2 were achieved. The protocol was effective for the preparation of the tricyclic iminosugar in satisfactory yield. The results of the glycosidase inhibitory activities of 1 and 2 showed that three compounds derived from d-ribose exhibited specific and good inhibitory effects on ß-glucosidase. Among them, 1e-1 was the best one with IC50 value of 5.37 µM. All hydroxyl groups on ß-position would be favourable to the inhibitory activity of such tricyclic benzimidazole-iminosugars against ß-glucosidase.

Neurofibromin (NF1) genetic variant structure-function analyses using a full-length mouse cDNA.

Neurofibromatosis type 1 (NF1) is caused by pathogenic variants or mutations in the NF1 gene that encodes neurofibromin. We describe here a new approach to determining the functional consequences of NF1 genetic variants. We established a heterologous cell culture expression system using a full-length mouse Nf1 cDNA (mNf1) and human cell lines. We demonstrate that the full-length murine cDNA produces a > 250 kDa neurofibromin protein that is capable of modulating Ras signaling. We created mutant cDNAs representing NF1 patient variants with different clinically relevant phenotypes, and assessed their ability to produce mature neurofibromin and restore Nf1 activity in NF1-/- cells. These cDNAs represent variants in multiple protein domains and various types of clinically relevant predicted variants. This approach will help advance research on neurofibromin structure and function, determine pathogenicity for missense variants, and allow for the development of activity assays and variant-directed therapeutics.

The Epigenome in Multiple Myeloma: Impact on Tumor Cell Plasticity and Drug Response.

Multiple myeloma (MM) is a clonal plasma cell malignancy that develops primarily in the bone marrow (BM), where reciprocal interactions with the BM niche foster MM cell survival, growth, and drug resistance. MM cells furthermore reshape the BM to their own needs by affecting the different BM stromal cell types resulting in angiogenesis, bone destruction, and immune suppression. Despite recent advances in treatment modalities, MM remains most often incurable due to the development of drug resistance to all standard of care agents. This underscores the unmet need for these heavily treated relapsed/refractory patients. Disruptions in epigenetic regulation are a well-known hallmark of cancer cells, contributing to both cancer onset and progression. In MM, sequencing and gene expression profiling studies have also identified numerous epigenetic defects, including locus-specific DNA hypermethylation of cancer-related and B cell specific genes, genome-wide DNA hypomethylation and genetic defects, copy number variations and/or abnormal expression patterns of various chromatin modifying enzymes. Importantly, these so-called epimutations contribute to genomic instability, disease progression, and a worse outcome. Moreover, the frequency of mutations observed in genes encoding for histone methyltransferases and DNA methylation modifiers increases following treatment, indicating a role in the emergence of drug resistance. In support of this, accumulating evidence also suggest a role for the epigenetic machinery in MM cell plasticity, driving the differentiation of the malignant cells to a less mature and drug resistant state. This review discusses the current state of knowledge on the role of epigenetics in MM, with a focus on deregulated histone methylation modifiers and the impact on MM cell plasticity and drug resistance. We also provide insight into the potential of epigenetic modulating agents to enhance clinical drug responses and avoid disease relapse.

Loss of RASSF4 Expression in Multiple Myeloma Promotes RAS-Driven Malignant Progression.

RAS mutations occur frequently in multiple myeloma (MM), but apart from driving progression, they can also stimulate antitumor effects by activating tumor-suppressive RASSF proteins. Although this family of death effector molecules are often silenced in cancers, functional data about RASSF proteins in MM are lacking. Here, we report that RASSF4 is downregulated during MM progression and correlates with a poor prognosis. Promoter methylation analysis in human cell lines revealed an inverse correlation between RASSF4 mRNA levels and methylation status. Epigenetic modulating agents restored RASSF4 expression. Enforced expression of RASSF4 induced G2-phase cell-cycle arrest and apoptosis in human cell lines, reduced primary MM cell viability, and blocked MM growth in vivo Mechanistic investigations showed that RASSF4 linked RAS to several pro-death pathways, including those regulated by the kinases MST1, JNK, and p38. By activating MST1 and the JNK/c-Jun pathway, RASSF4 sensitized MM cells to bortezomib. Genetic or pharmacological elevation of RASSF4 levels increased the anti-MM effects of the clinical relevant MEK1/2 inhibitor trametinib. Kinome analysis revealed that this effect was mediated by concomitant activation of the JNK/c-Jun pathway along with inactivation of the MEK/ERK and PI3K/mTOR/Akt pathways. Overall, our findings establish RASSF4 as a tumor-suppressive hub in MM and provide a mechanistic rationale for combining trametinib with HDAC inhibitors or bortezomib to treat patients with tumors exhibiting low RASSF4 expression.Significance: These findings provide a mechanistic rationale for combining trametinib with HDAC inhibitors or bortezomib in patients with multiple myeloma whose tumors exhibit low RASSF4 expression. Cancer Res; 78(5); 1155-68. ©2017 AACR.

In Vivo Imaging of Glutamine Metabolism to the Oncometabolite 2-Hydroxyglutarate in IDH1/2 Mutant Tumors.

The oncometabolite 2-hydroxyglutarate (2-HG) is a signature biomarker in various cancers, where it accumulates as a result of mutations in isocitrate dehydrogenase (IDH). The metabolic source of 2-HG, in a wide variety of cancers, dictates both its generation and also potential therapeutic strategies, but this remains difficult to access in vivo. Here, utilizing patient-derived chondrosarcoma cells harboring endogenous mutations in IDH1 and IDH2, we report that 2-HG can be rapidly generated from glutamine in vitro. Then, using hyperpolarized magnetic resonance imaging (HP-MRI), we demonstrate that in vivo HP [1-13C] glutamine can be used to non-invasively measure glutamine-derived HP 2-HG production. This can be readily modulated utilizing a selective IDH1 inhibitor, opening the door to targeting glutamine-derived 2-HG therapeutically. Rapid rates of HP 2-HG generation in vivo further demonstrate that, in a context-dependent manner, glutamine can be a primary carbon source for 2-HG production in mutant IDH tumors.

Complete humanization of the mouse immunoglobulin loci enables efficient therapeutic antibody discovery.

If immunized with an antigen of interest, transgenic mice with large portions of unrearranged human immunoglobulin loci can produce fully human antigen-specific antibodies; several such antibodies are in clinical use. However, technical limitations inherent to conventional transgenic technology and sequence divergence between the human and mouse immunoglobulin constant regions limit the utility of these mice. Here, using repetitive cycles of genome engineering in embryonic stem cells, we have inserted the entire human immunoglobulin variable-gene repertoire (2.7 Mb) into the mouse genome, leaving the mouse constant regions intact. These transgenic mice are viable and fertile, with an immune system resembling that of wild-type mice. Antigen immunization results in production of high-affinity antibodies with long human-like complementarity-determining region 3 (CDR3H), broad epitope coverage and strong signatures of somatic hypermutation. These mice provide a robust system for the discovery of therapeutic human monoclonal antibodies; as a surrogate readout of the human antibody response, they may also aid vaccine design efforts.

Evidence for dechlorination of polychlorinated biphenyls and polychlorinated dibenzo-p-dioxins and -furans in wastewater collection systems in the New York metropolitan area.

Polychlorinated biphenyls (PCBs) and polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) are persistent organic pollutants targeted by the Stockholm Convention. Both contain aromatic chlorines and are subject to microbial dechlorination. Dechlorination of PCBs in sewers in the Delaware River basin was recently reported. In this work, two data sets on concentrations of PCBs and PCBs+PCDD/Fs in wastewater treatment plant influents and effluents were analyzed to look for evidence that these compounds undergo dechlorination in the sewers of the New York/New Jersey Harbor area. The two data sets come from the Contamination Assessment and Reduction Project (CARP) and were analyzed via Positive Matrix Factorization (PMF). Analysis of the data set containing only PCB concentrations suggests that PCBs are dechlorinated in the sewers of the NY/NJ Harbor via the same pathways observed in the sewers of the Delaware River basin and that advanced dechlorination of PCB mixtures is more likely to occur in combined sewers vs separate sanitary sewers. When the combined data set of PCBs+PCDD/Fs was analyzed, the factor containing PCB dechlorination products also contained high proportions of 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD), a known product of the dechlorination of octachlorodibenzo-p-dioxin (OCDD), and other known dechlorination products of PCDD/Fs. Despite being the most abundant PCDD/F congener in all of the samples in the database, OCDD was a minor component in the dechlorination factor. This provides the first evidence that PCDD/Fs may be dechlorinated in sewers.

Experimental and modeling study of the effects of multicomponent gas additives on selective non-catalytic reduction process.

The influence of multicomponent additives on NO reduction by selective non-catalytic reduction process has been investigated experimentally in an electricity-heated tube reactor. The multicomponent additives are composed of two species of CO, CH(4) and H(2), and the molar ratio of their two components varies from 1/3 to 3/1. The results show that all the investigated additives could decrease the optimal temperature for NO reduction effectively, but the contributions of their components are different. The performance of multicomponent additive composed of CO and CH(4) depends mainly on CH(4) component. The function of CO component is shifting the temperature window for NO reduction to lower temperature slightly and narrowing the temperature window a little. The temperature window with multicomponent additive composed of H(2) and CH(4) is distinct from that with its each component, so both H(2) and CH(4) component make important contributions. While the fraction of CO is no more than that of H(2) in multicomponent additives composed of them, the performance of multicomponent additives is dominated by H(2) component; while the fraction of CO becomes larger, the influence of CO component becomes notable. Qualitatively the modeling results using a detailed chemical kinetic mechanism exhibit the same characteristics of the temperature window shift as observed experimentally. By reaction mechanism analysis, the distinct influences of CO, CH(4) or H(2) component on the property of multicomponent additive are mainly caused by the different production rates of (*)OH radical in their own oxidation process.

Lack of HIV testing and awareness of HIV infection among men who have sex with men, Beijing, China.

In China, men who have sex with men (MSM) are at high risk for HIV. However, little is known about their HIV testing behavior. From September 2001 to January 2002, we recruited 482 men through social networks and MSM venues. We conducted HIV testing and counseling, and anonymous, standardized face-to-face interviews. Eighty-two percent of participants had never tested for HIV before the study. The most common reasons for not testing were perceived low risk of HIV infection (72%), not knowing the location of test sites (56%), fear of positive test results (54%), fear of people learning about his homosexuality (47%), and fear of breach of confidentiality about test results (47%). We identified five statistically significant independent correlates of having been tested for HIV: being older, having a college degree, being more "out" (disclosing MSM activities to people), being recruited through social networks, and having a lifetime history of sexually transmitted diseases. Of 15 participants (3.1%) who tested positive for HIV in our study, 14 (93%) did not know their status before being tested in the study. The prevalence of HIV testing among MSM in Beijing is low; almost all HIV-positive men in our study were unaware of their infection. Our findings suggest an urgent need to promote HIV testing among MSM in Beijing.

[Knowledge discovery in database and its application in clinical diagnosis].

Nowadays the tremendous amount of data has far exceeded our human ability for comprehension, and this has been particularly true for the medical database. However, traditional statistical techniques are no longer adequate for analyzing this vast collection of data. Knowledge discovery in database and data mining play an important role in analyzing data and uncovering important data patterns. This paper briefly presents the concepts of knowledge discovery in database and data mining, then describes the rough set theory, and gives some examples based on rough set.

Targeted expression of IGF-1 transgene to skeletal muscle accelerates muscle and motor neuron regeneration.

Currently, there is no known medical treatment that hastens the repair of damaged nerve and muscle. Using IGF-1 transgenic mice that specifically express human recombinant IGF-1 in skeletal muscle, we test the hypotheses that targeted gene expression of IGF-1 in skeletal muscle enhances motor nerve regeneration after a nerve crush injury. The IGF-1 transgene affects the initiation of the muscle repair process after nerve injury as shown by increased activation of SCA-1positive myogenic stem cells. Increased satellite cell differentiation and proliferation are observed in IGF-1 transgenic mice, shown by increased expression of Cyclin D1, MyoD, and myogenin. Expression of myogenin and nicotinic acetylcholine receptor subunits, initially increased in both wild-type and IGF-1 transgenic mice, are restored to normal levels at a faster rate in IGF-1 transgenic mice, which indicates a rescue of nerve-evoked muscle activity. Expression of the IGF-1 transgene in skeletal muscle results in accelerated recovery of saltatory nerve conduction, increased innervation as detected by neurofilament expression, and faster recovery of muscle mass. These studies demonstrate that local expression of IGF-1 augments the repair of injured nerve and muscle.