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Sometimes, people can be exposed to moderate or high doses of radiation accidentally or through the environment. Radiation can cause great harm to several systems within organisms, especially the hematopoietic system. Several types of drugs protect the hematopoietic system against radiation damage in different ways. They can be classified as "synthetic drugs" and "natural compounds." Their cellular mechanisms to protect organisms from radiation damage include free radical-scavenging, anti-oxidation, reducing genotoxicity and apoptosis, and alleviating suppression of the bone marrow. These topics have been reviewed to provide new ideas for the development and research of drugs alleviating radiation-induced damage to the hematopoietic system.

Epstein-Barr virus (EBV) is associated with a range of epithelial and B cell malignancies as well as autoimmune disorders, for which there are still no specific treatments or effective vaccines. Here, we isolate EBV gH/gL-specific antibodies from an EBV-infected individual. One antibody, 1D8, efficiently neutralizes EBV infection of two major target cell types, B cells and epithelial cells. In humanized mice, 1D8 provides protection against a high-dose EBV challenge by substantially reducing viral loads and associated tumor burden. Crystal structure analysis reveals that 1D8 binds to a key vulnerable interface between the D-I/D-II domains of the viral gH/gL protein, especially the D-II of the gH, thereby interfering with the gH/gL-mediated membrane fusion and binding to target cells. Overall, we identify a potent and protective neutralizing antibody capable of reducing the EBV load. The novel vulnerable site represents an attractive target that is potentially important for antibody and vaccine intervention against EBV infection., Currently, there are no treatments or vaccines against Epstein-Barr virus (EBV) infection. Here, Zhu et al. isolate gH/gL-specific antibodies from infected donors and identify 1D8, that substantially reduces infection levels in both, B- and epithelial cells, and reduces tumor burdens in EBV-challanged humanized mice due to interferance with the gH/gL-mediated membrane fusion and binding.

Kashin–Beck disease (KBD) is an endemic disease in China with the highest incidence rate in Tibet region. Promoted generation of oxygen free radicals by semiquinone structure of humic substance (HS) in drinking water was considered to be one of its pathogeneses. Therefore, detailed analysis of HS was performed in water and sediment samples collected from three endemic and three disease-free areas in Changdu Region, Tibet, China. After purification of the HS in the samples, the fractions of HS were characterized using electron paramagnetic resonance, 13C nuclear magnetic resonance, fluorescence spectroscopy with parallel factor analysis and Fourier transform infrared spectroscopy (FTIR). The organic carbon content of HS did not show a significant difference between endemic and disease-free areas or correlation with KBD-associated morbidity. Except FTIR, all techniques succeeded in characterization of the quinone redox system, indicating their validity and consistency. The quinone redox system in aquatic HS exhibited significantly higher level of the following indexes in endemic areas than disease-free areas: semiquinone radical content of fulvic acid (FA) (p

Siglec-7 (sialic acid–binding immunoglobulin-like lectin 7) is an immune checkpoint-like glycan recognition protein on natural killer (NK) cells. Cancer cells often upregulate Siglec ligands to subvert immunosurveillance, but the molecular basis of Siglec ligands has been elusive. In this study, we investigated Siglec-7 ligands on chronic lymphocytic leukemia (CLL) B cells. CLL B cells express higher levels of Siglec-7 ligands compared with healthy donor B cells, and enzymatic removal of sialic acids or sialomucins makes them more sensitive to NK cell cytotoxicity. Gene knockout experiments have revealed that the sialyltransferase ST6GalNAc-IV is responsible for the biosynthesis of disialyl-T (Neu5Acα2–3Galβ1–3[Neu5Acα2–6]GalNAcα1–), which is the glycotope recognized by Siglec-7, and that CD162 and CD45 are the major carriers of this glycotope on CLL B cells. Analysis of public transcriptomic datasets indicated that the low expression ofGCNT1(encoding core 2 GlcNAc transferase, an enzyme that competes against ST6GalNAc-IV) and high expression ofST6GALNAC4(encoding ST6GalNAc-IV) in CLL B cells, together enhancing the expression of the disialyl-T glycotope, are associated with poor patient prognosis. Taken together, our results determined the molecular basis of Siglec-7 ligand overexpression that protects CLL B cells from NK cell cytotoxicity and identified disialyl-T as a potential prognostic marker of CLL.

In recent years, studies have shown that exposure to environmental pollutants (e.g., radiation, heavy metal substances, air pollutants, organic pollutants) is a leading cause of human non-communicable diseases. The key to disease prevention is to clarify the harmful mechanisms and toxic effects of environmental pollutants on the body. Metabolomics is a high-sensitivity, high-throughput omics technology that can obtain detailed metabolite information of an organism. It is a crucial tool for gaining a comprehensive understanding of the pathway network regulation mechanism of the organism. Its application is widespread in many research fields such as environmental exposure assessment, medicine, systems biology, and biomarker discovery.Recent findings show that metabolomics can be used to obtain molecular snapshots of organisms after environmental exposure, to help understand the interaction between environmental exposure and organisms, and to identify potential biomarkers and biological mechanisms.This review focuses on the application of metabolomics to understand the biological effects of radiation, heavy metals, air pollution, and persistent organic pollutants exposure, and examines some potential biomarkers and toxicity mechanisms.

Background The SARS-CoV-2 containment strategy has been successful in mainland China prior to the emergence of Omicron. However, in the era of highly transmissible variants, whether it is possible for China to sustain a local containment policy and under what conditions China could transition away from it are of paramount importance at the current stage of the pandemic. Methods We developed a spatially structured, fully stochastic, individual-based SARS-CoV-2 transmission model to evaluate the feasibility of sustaining SARS-CoV-2 local containment in mainland China considering the Omicron variants, China’s current immunization level, and nonpharmaceutical interventions (NPIs). We also built a statistical model to estimate the overall disease burden under various hypothetical mitigation scenarios. Results We found that due to high transmissibility, neither Omicron BA.1 nor BA.2 could be contained by China’s pre-Omicron NPI strategies which were successful prior to the emergence of the Omicron variants. However, increased intervention intensity, such as enhanced population mobility restrictions and multi-round mass testing, could lead to containment success. We estimated that an acute Omicron epidemic wave in mainland China would result in significant number of deaths if China were to reopen under current vaccine coverage with no antiviral uptake, while increasing vaccination coverage and antiviral uptake could substantially reduce the disease burden. Conclusions As China’s current vaccination has yet to reach high coverage in older populations, NPIs remain essential tools to maintain low levels of infection while building up protective population immunity, ensuring a smooth transition out of the pandemic phase while minimizing the overall disease burden.

Tisagenlecleucel is a CD19 chimeric antigen receptor (CAR) T-cell therapy approved for treatment of pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia (ALL) and adults with non-Hodgkin lymphoma (NHL). The initial experience with tisagenlecleucel in a real-world setting from a cellular therapy registry is presented here. As of January 2020, 511 patients were enrolled from 73 centers, and 410 patients had follow-up data reported (ALL, n = 255; NHL, n = 155), with a median follow-up of 13.4 and 11.9 months for ALL and NHL, respectively. Among patients with ALL, the initial complete remission (CR) rate was 85.5%. Twelve-month duration of response (DOR), event-free survival, and overall survival (OS) rates were 60.9%, 52.4%, and 77.2%, respectively. Among adults with NHL, the best overall response rate was 61.8%, including an initial CR rate of 39.5%. Six-month DOR, progression-free survival, and OS rates were 55.3%, 38.7%, and 70.7%, respectively. Grade ≥3 cytokine release syndrome and neurotoxicity were reported in 11.6% and 7.5% of all patients, respectively. Similar outcomes were observed in patients with in-specification and out-of-specification products as a result of viability

This study determined the effect of divided attention on controlling postural stability during a drop vertical jump task. In total, 30 participants were tested for drop vertical jumps from a 30-cm high platform and landing on a single leg with or without divided attention tasks. Three-dimensional marker trajectories and ground reaction forces were collected simultaneously. Vertical ground reaction force, loading rate, and dynamic postural stability index were analyzed with or without divided attention tasks. The paired sample t test indicated a significantly low knee flexion angle, high vertical ground reaction force, and increased loading rate in the divided attention task. Moreover, participants showed an increased vertical stability index and dynamic postural stability index in the divided attention task than in the nondivided attention task. Thus, results demonstrated that the divided attention task could affect posture control, leading to poor dynamic posture stability and possibly increasing lower extremity injury risk. The influence of the divided attention task on movement quality likely indicates that an athlete can no longer focus his attention on the bounce drop jump maneuver. Therefore, the bounce drop jump combined with dynamic postural stability index could be used in posture stability screening.

The persistent COVID-19 pandemic since 2020 has brought an enormous public health burden to the global society and is accompanied by various evolution of the virus genome. The consistently emerging SARS-CoV-2 variants harboring critical mutations impact the molecular characteristics of viral proteins and display heterogeneous behaviors in immune evasion, transmissibility, and the clinical manifestation during infection, which differ each strain and endow them with distinguished features during populational spread. Several SARS-CoV-2 variants, identified as Variants of Concern (VOC) by the World Health Organization, challenged global efforts on COVID-19 control due to the rapid worldwide spread and enhanced immune evasion from current antibodies and vaccines. Moreover, the recent Omicron variant even exacerbated the global anxiety in the continuous pandemic. Its significant evasion from current medical treatment and disease control even highlights the necessity of combinatory investigation of the mutational pattern and influence of the mutations on viral dynamics against populational immunity, which would greatly facilitate drug and vaccine development and benefit the global public health policymaking. Hence in this review, we summarized the molecular characteristics, immune evasion, and impacts of the SARS-CoV-2 variants and focused on the parallel comparison of different variants in mutational profile, transmissibility and tropism alteration, treatment effectiveness, and clinical manifestations, in order to provide a comprehensive landscape for SARS-CoV-2 variant research.

Anthropogenic and natural factors lead to substantial environmental degradation. This shift is aligned with the country's overall development, resulting in high demand for energy resources and a dramatic shift in human activities that contribute to haze pollution. Some of the countries in the South Asian region are ranked between one and twenty on the list of countries with the highest levels of PM2.5 pollution. The member countries have taken many steps to tackle global warming, but concern about haze pollution was found limited. Moreover, very little research was conducted on haze pollution, which led us to conduct this research in this region. This study used the panel data from 1998 to 2018 and a set of econometric models like long-term cointegrating relationship, fully modified ordinary least squares, and vector error-correction model Granger causality tests to examine the major drivers like anthropogenic and natural factors that might elevate haze pollution. Furthermore, our empirical results depict that (1) there is a long-term cointegrating relation between haze and the factors studied. (2) Energy consumption, urbanisation, and economic growth are the primary drivers of environmental degradation. (3) Rainfall has the most substantial influence on reducing haze pollution. The study concluded that (a) if the countries continue to develop at the same pace, all factors studied will continue to drive haze pollution to rise. (b) A decrease in PM2.5 pollution requires improvements in regional rainfall through vegetation, reducing reliance on fossil fuel-based energy sources, and increasing environmental education. (c) Slowing down the drive for urbanisation would not be cost-effective in reducing haze pollution in the region in the short run. Thus, reducing haze by adjusting the factors studied would not be easy in the short run and require the careful adoption of long-term policies.

Siglecs, a family of receptor-like lectins, recognize glycoproteins and/or glycolipids containing sialic acid in the extracellular space and transduce intracellular signaling. Recently, researchers uncovered significant contributions of Siglecs in cancer immunity, renewing interest in this family of proteins. Previous extensive studies have defined how Siglecs recognize glycan epitopes (glycotopes). Nevertheless, the biological role of these glycotopes has not been fully evaluated. Recent studies using live cells have begun unraveling the constituents of Siglec ligands. These studies demonstrated that glycoprotein scaffolds (counter-receptors) displaying glycotopes are sometimes just as important as the glycotope itself. These new insights may guide future efforts to develop therapeutic agents to target the Siglec – ligand axis.

Background Helminths are endemic in more than half of the world’s countries, raising serious public health concerns. Accurate diagnosis of helminth infection is crucial to control strategies. Traditional parasitological methods, serological tests and PCR-based assays are the major means of the diagnosis of helminth infection, but they are time-consuming and/or expensive, and sometimes provide inaccurate results. Loop mediated isothermal amplification (LAMP) assay, a sensitive, simple and rapid method was therefore developed for detection of helminths. This study aims to discuss the current status of application of LAMP on helminths detection and to make a comprehensive evaluation about this updated technology and its future outlook by comparing with several other diagnostic methods. Main body This review summarizes LAMP assay applied for helminth detection and helminthiasis surveillance. The basic principle of LAMP is introduced to help better understand its characteristics and each reported assay is assessed mainly based on its detection sensitivity, specificity and limitations, in comparison with other common diagnostic tests. Moreover, we discuss the limitations of the assays so as to clarify some potential ways of improvement. Conclusions Here, we summarize and discuss the advantages, disadvantages and promising future of LAMP in heliminth detection, which is expected to help update current knowledge and future perspectives of LAMP in highly sensitive and specific diagnosis and surveillance of helminthiasis and other parasitic diseases, and can contribute to the elimination of the diseases from endemic areas. Electronic supplementary material The online version of this article (10.1186/s40249-019-0530-z) contains supplementary material, which is available to authorized users.

A miniature tyrosinase-based electrochemical sensing platform for label-free detection of protein tyrosine kinase activity was developed in this study. The developed miniature sensing platform can detect the substrate peptides for tyrosine kinases, such as c-Src, Hck and Her2, in a low sample volume (1–2 μL). The developed sensing platform exhibited a high reproducibility for repetitive measurement with an RSD (relative standard deviation) of 6.6%. The developed sensing platform can detect the Hck and Her2 in a linear range of 1–200 U/mL with the detection limit of 1 U/mL. The sensing platform was also effective in assessing the specificity and efficacies of the inhibitors for protein tyrosine kinases. This is demonstrated by the detection of significant inhibition of Hck (~88.1%, but not Her2) by the Src inhibitor 1, an inhibitor for Src family kinases, as well as the significant inhibition of Her2 (~91%, but not Hck) by CP-724714 through the platform. These results suggest the potential of the developed miniature sensing platform as an effective tool for detecting different protein tyrosine kinase activity and for accessing the inhibitory effect of various inhibitors to these kinases.

The impact of long-term low-dose radiation on human health has always been a concern. Long-term low-dose gamma radiation causes cells continuous injury and causes chromosomal mutations to greatly increase the chance of cancer. Because it is significant to identify biomarkers for long-term low-dose gamma radiation, we investigate the influence of low dose rate on the gene expressions in the AHH-1 lymphocytes cell line (AHH-1 cells) for long-term irradiation. Different dose rates (7, 14, 26, 34, and 43 μGy h-1) of irradiation from gamma radiation in uranium tailings powder were used to irradiate AHH-1 lymphocytes. We used flow cytometry to test the apoptosis of AHH-1 lymphocytes at different dose rates and irradiation times (7-84 d). It was found that 14 μGy h-1 is the most sensitive dose rate of AHH-1 lymphocyte irradiation. The 7-, 14-, and 21-d (2.4, 4.8, and 7.2 mGy) irradiation groups were sensitive, and the 84-d (28.8 mGy) irradiation group was insensitive to low dose gamma radiation. Microarray analysis was conducted on the significantly differentially expressed genes (p

Ionizing radiation (IR) is a form of high energy. It poses a serious threat to organisms, but radiotherapy is a key therapeutic strategy for various cancers. It is significant to reduce radiation injury but maximize the effect of radiotherapy. MicroRNAs (miRNAs) are posttranscriptionally regulatory factors involved in cellular radioresponse. In this review, we show how miRNAs regulate important genes on cellular response to IR-induced damage and how miRNAs participate in IR-induced carcinogenesis. Additionally, we summarize the experimental and clinical evidence for miRNA involvement in radiotherapy and discuss their potential for improvement of radiotherapy. Finally, we highlight the role that miRNAs play in accident exposure to IR or radiotherapy as predictive biomarker. miRNA therapeutics have shown great perspective in radiobiology; miRNA may become a novel strategy for damage and protection against IR.

ForNinety-nine patients who underwentIn total, 113 abnormal parathyroid lesions were identified on the SPECT/CT images. The agreements of interpretation between the two image sets and readers were very good (κ value: 0.83-1.00). The accuracies of summative interpretation for the anterior 180° and full-arc 360° SPECT/CT were 83.04% and 82.46%, respectively. The target-to-background ratios were significantly higher for the anterior 180° than the full-arc 360° images (P 0.01).The anterior 180° SPECT/CT technique, a time-saving method, can provide satisfactory diagnostic performance and superior lesion contrast compared with the full-arc 360° SPECT/CT technique in

Summary Fibrosis, or the accumulation of extracellular matrix, is a common feature of many chronic diseases. To interrogate core molecular pathways underlying fibrosis, we cross-examine human primary cells from various tissues treated with TGF-β, as well as kidney and liver fibrosis models. Transcriptome analyses reveal that genes involved in fatty acid oxidation are significantly perturbed. Furthermore, mitochondrial dysfunction and acylcarnitine accumulation are found in fibrotic tissues. Substantial downregulation of the PGC1α gene is evident in both in vitro and in vivo fibrosis models, suggesting a common node of metabolic signature for tissue fibrosis. In order to identify suppressors of fibrosis, we carry out a compound library phenotypic screen and identify AMPK and PPAR as highly enriched targets. We further show that pharmacological treatment of MK-8722 (AMPK activator) and MK-4074 (ACC inhibitor) reduce fibrosis in vivo. Altogether, our work demonstrate that metabolic defect is integral to TGF-β signaling and fibrosis., Graphical Abstract, Highlights Profiling of multiple fibrosis models reveals a common fatty acid oxidation defect Downregulation of PGC1α expression in both in vitro and in vivo fibrosis models Compound library screen identifies AMPK and PPAR as enriched targets for fibrosis MK-8722 and MK-4074 treatment reduces liver fibrosis in a NASH model, Fibrosis, also known as scarring of the tissue, is a common feature of many chronic diseases. Zhang et al. combine transcriptome profiling, metabolomics, metabolic flux analyses, and high-throughput compound library phenotypic screening to show that metabolic defect is a common feature of tissue fibrosis.

Cytokine release syndrome (CRS) is a systemic inflammatory response associated with chimeric antigen receptor T-cell (CAR-T) therapies. In severe cases, CRS can be associated with coagulopathy and hypofibrinogenemia. We present our global multicenter experience with CRS-associated coagulopathy after tisagenlecleucel therapy in 137 patients with relapsed or refractory B-cell acute lymphoblastic leukemia from the ELIANA and ENSIGN trials. These trials included clinical guidelines for fibrinogen replacement during CRS-associated coagulopathy. Hypofibrinogenemia requiring replacement was observed only in patients with severe CRS. A higher percentage of patients who required replacement were

Siglecs are transmembrane receptor-like vertebrate lectins that recognize glycans containing sialic acid. Most Siglecs also interact with intracellular signal transduction molecules, and modulate immune responses. Recombinant soluble Siglecs fused with the fragment crystallizable (Fc) region of immunoglobulin G (Siglec-Fc) are a versatile tool for the investigation of Siglec functions. We describe protocols for the production of recombinant Siglec-Fc, the analysis of expression of Siglec ligands by flow cytometry, and the identification of the Siglec ligand candidates based on proximity labeling.

Diallyl disulfide (DADS), the main active component of the cancer fighting allyl sulfides found in garlic, has shown potential as a therapeutic agent in various cancers. Previous studies showed DADS induction of HL‐60 cell differentiation involves down‐regulation of calreticulin (CRT). Here, we investigated the mechanism of DADS‐induced differentiation of human leukaemia cells and the potential involvement of CRT and CCAAT enhancer binding protein‐α (C/EBPα). We explored the expression of CRT and C/EBPα in clinical samples (20 healthy people and 19 acute myeloid leukaemia patients) and found that CRT and C/EBPα expressions were inversely correlated. DADS induction of differentiation of HL‐60 cells resulted in down‐regulated CRT expression and elevated C/EBPα expression. In severe combined immunodeficiency mice injected with HL‐60 cells, DADS inhibited the growth of tumour tissue and decreased CRT levels and increased C/EBPα in vivo. We also found that DADS‐mediated down‐regulation of CRT and up‐regulation of C/EBPα involved enhancement of reactive oxidative species. RNA immunoprecipitation revealed that CRT bound C/EBPα mRNA, indicating its regulation of C/EBPα mRNA degradation by binding the UG‐rich element in the 3′ untranslated region of C/EBPα. In conclusion, the present study demonstrates the C/EBPα expression was correlated with CRT expression in vitro and in vivo and the molecular mechanism of DADS‐induced leukaemic cell differentiation.

Global consumption of disposable plastic tableware (DPT) is massive because it is durable, light and inexpensive. Using the life cycle assessment method, we found that DPT for per person per meal emitted 597 g of CO2 and was far more than that of reusable plastic tableware (RPT, 7.00 g), ceramic tableware (9.55 g) and straw tableware (14.6 g). If the demand growth for DPT continues, 416 MT of CO2 will be emitted due to DPT consumption by 2050 globally. We further explored strategies to reduce CO2 emissions by examining the life cycles of four types of tableware according to sensitivity analysis. According to our results, if the recycling rate of DPT reaches 60% at the end-of-life stage, 50% of CO2 emissions can be cut; if dishwashing instead of hand washing is used to clean RPT, ceramic, and straw tableware, approximately 64%, 71%, and 23% of CO2 emissions can be reduced, respectively. If 60% of DPT is replaced by RPT, this plastic tableware will halve carbon emissions. If the rate reaches 100%, carbon emissions will be reduced by 92%. Although the CO2 emissions of the three types of tableware other than DPT are relatively small, RPT will bring other environmental burdens and human health risks, ceramic tableware is bulky and its additives are toxic. Straw tableware combines practical and safety performance. The results show that the choice of straw tableware plays a significant role in curbing the greenhouse effect without compromising consumer safety.

Siglecs are a family of receptor-type glycan recognition proteins (lectins) involved in self-nonself discrimination by the immune system. Identification of Siglec ligands is necessary to understand how Siglec-ligand interaction translates into biological outcomes. However, this is challenging because the interaction is weak. To facilitate identification of Siglec ligands, we adopted a proximity labeling method based on the tyramide radicalization principle. Cells that express Siglec ligands were labeled with Siglec-peroxidase complexes and incubated with biotin tyramide and hydrogen peroxide to generate short-lived tyramide radicals that covalently label the proteins near the Siglec-peroxidase complex. A proof-of-principle experiment using CD22 (Siglec-2) probe identified its known ligands on B cells, including CD22 itself, CD45, and IgM, among others, demonstrating the validity of this method. The specificity of labeling was confirmed by sialidase treatment of target cells and using glycan recognition-deficient mutant CD22 probes. Moreover, possible interactions between biotin-labeled proteins were revealed by literature-based protein-protein interaction network analysis, implying the presence of a molecular cluster comprising CD22 ligands. Further application of this method identified CD44 as a hitherto unknown Siglec-15 ligand on RAW264.7-derived osteoclasts. These results demonstrated the utility of proximity labeling for the identification of Siglec ligands, which may extend to other lectins.

Glutathione S‑transferase Pi (GSTP1) is an isozyme encoded by the GST pi gene that plays an important regulatory role in detoxification, anti‑oxidative damage, and the occurrence of various diseases. The aim of the present study was to review the association between the expression of GSTP1 and the development and treatment of various cancers, and discuss GSTP1 methylation in several malignant tumors, such as prostate, breast and lung cancer, as well as hepatocellular carcinoma; to review the association between polymorphism of the GSTP1 gene and various diseases; and to review the effects of GSTP1 on electrophilic oxidative stress, cell signal transduction, and the regulation of carcinogenic factors. Collectively, GSTP1 plays a major role in the development of various diseases.

Background: Food safety incidents have aroused widespread public health concern, causing food price risk. However, the causal paths remain largely unexplored in previous literature. This paper sets out to identify the relations of local and spatial spillovers of food safety incidents and public health concerns to food price risk in consumer markets within a setting with heterogeneous food safety risk levels. Methods: (i) Theoretically, unlike prior work, this paper decomposes food safety risks into food safety incidents (objective incident component) and public health concern (subjective concern component). This article develops a theoretical framework of causality to capture the underlying causal pathways motivated by the theories of limited attention and two-step flow of communication. (ii) Empirically, using avian influenza shocks in China&rsquo, s poultry markets as natural experiments, this paper differentiates between low- and high-risk food and incidents. The article adopts dynamic spatial panel models to analyze potential nonlinearity, moderation, and mediation in the spillover of food safety risk to food price risk for a long panel of 30 provinces covering the November 2007 to November 2017 period. Results: (i) Food safety incident alone only triggers high-risk food price risk, not low-risk food price risk. (ii) Public health concern amplifies nonlinear food price risk triggered by food safety incident. (iii) High-risk incident intensifies negative pressure of public health concern on food price risk. (iv) Food safety incident indirectly affects high-risk food price risk through public health concern. Conclusions: Using a setting with heterogeneous risk levels, this paper documents that (i) food safety incident itself does not necessarily determine food price risk, whereas it is actually public health concern that directly causes nonlinear food price risk, (ii) public health concern spillover to food price risk is negatively moderated by high-risk incident, and (iii) food safety incident spillover to high-risk food price risk is mediated by public health concern. The findings complement current research by (i) elucidating the diverse impacts of food safety incident and public health concern on food price risk, which are obscure in previous literature, and (ii) highlighting that heterogeneous food and incident risk levels matter for determining food price risk spillover.

Cofilin is associated with cell differentiation; however, to the best of our knowledge, no data have indicated an association between the cofilin 1 pathway and leukemia cell differentiation. The present study investigated the involvement of the cofilin 1 signaling pathway in diallyl disulfide (DADS)‑induced differentiation and the inhibitory effects on the proliferation, migration, and invasion of human leukemia HL‑60 cells. First, it was identified that 8 µM DADS suppressed cell proliferation, migration and invasion, and induced differentiation based on the reduced nitroblue tetrazolium ability and increased CD11b and CD33 expression. DADS significantly downregulated the expression of cofilin 1 and phosphorylated cofilin 1 in HL‑60 leukemia cells. Second, it was verified that silencing cofilin 1 markedly promoted 8 µM DADS‑induced differentiation and the inhibitory effect on cell proliferation and invasion. Overexpression of cofilin 1 obviously suppressed 8 µM DADS‑induced differentiation and the inhibitory effect on cell proliferation and invasion. Third, the present study examined the mechanisms by which 8 µM DADS decreases cofilin 1 expression and activation. The results revealed that 8 µM DADS inhibited the mRNA and protein expression of Rac1, Rho‑associated protein kinase 1 (ROCK1) and LIM domain kinase 1 (LIMK1) as well as the phosphorylation of LIMK1 in HL‑60 cells, while 8 µM DADS enhanced the effects of the Rac1‑ROCK1‑LIMK1 pathway in cells overexpressing cofilin 1 compared with that in control HL‑60 cells. These results suggest that the anticancer function of DADS on HL‑60 leukemia cells is regulated by the Rac1‑ROCK1‑LIMK1‑cofilin 1 pathway, indicating that DADS could be a promising anti‑leukemia therapeutic compound.

Diallyl disulfide (DADS) is a primary component of garlic, which has chemopreventive potential. We previously found that moderate doses (15-120 µM) of DADS induced apoptosis and G2/M phase cell cycle arrest. In this study, we observed the effect of low doses (8 µM) of DADS on human leukemia HL-60 cells. We found that DADS could inhibit proliferation, migration and invasion in HL-60 cells, and arrested cells at G0/G1 stage. Then, cell differentiation was displayed by morphologic observation, NBT reduction activity and CD11b evaluation of cytometric flow. It showed that DADS induced differentiation, reduced the ability of NBT and increased CD11b expression. Likewise, DADS inhibited xenograft tumor growth and induced differentiation in vivo. In order to make sure how DADS induced differentiation, we compared the protein expression profile of DADS-treated cells with that of untreated control. Using high resolution mass spectrometry, we identified 18 differentially expressed proteins after treatment with DADS, including four upregulated and 14 downregulated proteins. RT-PCR and western blot assay showed that DJ-1, cofilin 1, RhoGDP dissociation inhibitor 2 (RhoGDI2), Calreticulin (CTR) and PCNA were decreased by DADS. These data suggest that the effects of DADS on leukemia may be due to multiple targets for intervention.

Diallyl disulfide (DADS) has been demonstrated to exert potent anticancer effects in vitro and in vivo. Previous studies indicate that DADS may induce the differentiation and/or apoptosis of human leukemia cells in vitro. However, the mechanisms underlying these anticancer effects remain elusive. The aim of the present study was to investigate alterations in the subcellular localization of protein deglycase DJ-1 (also known as Parkinsonism associated deglycase-7, PARK-7) in the cytoplasm, nucleus and mitochondria of human leukemia HL-60 cells induced by DADS, in order to provide novel experimental evidence for the molecular mechanisms underlying the anticancer mechanisms of DADS in leukemia cells. HL-60 cells induced by DADS were collected at different time points, and proteins from the cytoplasm, nucleus and mitochondria of the cells were isolated using specific cellular component isolation kits. The protein expression levels of DJ-1 in these subcellular fractions of HL60 cells following exposure to DADS for varying lengths of time, were determined using western blotting, immunocytochemistry and immunofluorescence techniques. Following exposure of HL-60 cells to 1.25 mg/l DADS for 8 h, the protein expression levels of DJ-1 were significantly decreased in the cytoplasm, while nuclear fractions exhibited a significant increase in DJ-1 expression when compared with untreated controls. The protein expression levels of DJ-1 in mitochondria of HL-60 cells were significantly decreased following treatment with 5 and 10 mg/l DADS. These results demonstrate that exposure of HL-60 cells to low concentrations of DADS may promote DJ-1 protein translocation from the cytoplasm to the nucleus, which suggests that DJ-1 may function as a transcription factor or cofactor binding protein in the process of cell differentiation. The expression of DJ-1 in mitochondria may be associated with induction of apoptosis in HL-60 cells treated with moderate doses of DADS.

The study aimed to determine the relationships between the basal metabolic rate (BMR) and body composition of overweight and obese Chinese adults with type 2 diabetes mellitus (DM). This cross-sectional clinical study enrolled 193 Chinese adults with type 2 DM who were overweight (24 kg/m(2)=BMI≤28 kg/m(2), n=99), or obese (BMI ≥28 kg/m(2), n=94). Ninety-seven adults with normal BMIs, including 50 DM patients and 47 healthy adults, were recruited as a control group. BMR was measured by indirect calorimetry; predicted BMR was calculated according to the Schofield equation; and the relationships between BMR, body composition, and biochemical results were determined by the Pearson correlation. The results showed that obese DM patients had significantly higher BMRs than both overweight patients (P

Sialic acid (Sia)-binding immunoglobulin-like lectin 7 (Siglec-7) is an inhibitory receptor primarily expressed on natural killer (NK) cells and monocytes. Siglec-7 is known to negatively regulate the innate immune system through Sia binding to distinguish self and nonself; however, a counter-receptor bearing its natural ligand remains largely unclear. Here, we identified a counter-receptor of Siglec-7 using K562 hematopoietic carcinoma cells presenting cell surface ligands for Siglec-7. We affinity-purified the ligands using Fc-ligated recombinant Siglec-7 and diSia-dextran polymer, a strong inhibitor for Siglec-7. We then confirmed the counter-receptor for Siglec-7 as leukosialin (CD43) through mass spectrometry, immunoprecipitation, and proximity labeling. Additionally, we demonstrated that the cytotoxicity of NK cells toward K562 cells was suppressed by overexpression of leukosialin in a Siglec-7-dependent manner. Taken together, our data suggest that leukosialin on K562 is a counter-receptor for Siglec-7 on NK cells and that a cluster of the Sia-containing glycan epitope on leukosialin is key as trans-ligand for unmasking the cis-ligand.

Background: During zoonotic disease shocks (ZDSs), zoonotic disease outbreaks (ZDOs) can induce public health scares (PHSs), causing meat price risks (MPRs). Nevertheless, spatial spillovers of zoonotic disease shocks in meat markets remain unclear. We explore how zoonotic disease outbreaks and public health scares locally and spatially spill over to meat price risks, and whether spatial spillovers of public health scares decay with distance. Methods: (i) We construct a long panel covering 30 provinces and 121 months, using highly pathogenic avian influenza (HPAI) epidemics as exogenous shocks in Chinese meat sector. (ii) We decompose zoonotic disease shocks into zoonotic disease outbreaks (objective incident) and public health scares (subjective information) and examine their spillovers to meat price risks. (iii) We identify distance-decaying spatial spillovers of public health scares, by running our dynamic SAR models 147 times, from 80 km to 3000 km with 20 km as incremental value, in a setting with risk-level heterogeneity. Results: (i) Zoonotic disease outbreaks themselves only cause local and neighboring meat price risks for high-risk meat, not for low-risk or substitute meat. (ii) Public health scares exacerbate local and neighboring meat price risks for high-risk and low-risk meat, and local meat price risks for substitute meat. (iii) Spatial spillovers of public health scares are distance-decaying and U-shaped, with four spatial attenuation boundaries, and distance turning point is shorter for high-risk meat (500 km) than for low-risk meat (800 km). Conclusions: We complement the literature by arguing that health scares induced by disease outbreaks negatively spill over to meat prices, with U-shaped distance-decaying spatial effects. This suggests low interregional spatial market integration in meat products, due to distance decay of nonstandardized information and local government control effects, across provincial boundaries. To the best of our knowledge, we are the first to document nonmonotonic distance decay of health scare effects on food prices, previously not found by the literature.

Made available in DSpace on 2019-10-04T12:41:37Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-07-02 National Health and Medical Research Council of Australia Background-The uptake of proven stroke treatments varies widely. We aimed to determine the association of evidence-based processes of care for acute ischemic stroke (AIS) and clinical outcome of patients who participated in the HEADPOST (Head Positioning in Acute Stroke Trial), a multicenter cluster crossover trial of lying flat versus sitting up, head positioning in acute stroke. Methods and Results-Use of 8 AIS processes of care were considered: reperfusion therapy in eligible patients; acute stroke unit care; antihypertensive, antiplatelet, statin, and anticoagulation for atrial fibrillation; dysphagia assessment; and physiotherapist review. Hierarchical, mixed, logistic regression models were performed to determine associations with good outcome (modified Rankin Scale scores 0-2) at 90 days, adjusted for patient and hospital variables. Among 9485 patients with AIS, implementation of all processes of care in eligible patients, or defect-free care, was associated with improved outcome (odds ratio, 1.40; 95% CI, 1.18-1.65) and better survival (odds ratio, 2.23; 95% CI, 1.62-3.09). Defect-free stroke care was also significantly associated with excellent outcome (modified Rankin Scale score 0-1) (odds ratio, 1.22; 95% CI, 1.04-1.43). No hospital characteristic was independently predictive of outcome. Only 1445 (15%) of eligible patients with AIS received all processes of care, with significant regional variations in overall and individual rates. Conclusions-Use of evidence-based care is associated with improved clinical outcome in AIS. Strategies are required to address regional variation in the use of proven AIS treatments. Univ New South Wales, Fac Med, George Inst Global Hlth, Sydney, NSW, Australia Ctr Estudios Clin, Inst Ciencias & Innovac Med, Santiago, Chile Clin Alemana Univ Desarrollo, Fac Med, Serv Neurol, Dept Neurol & Psiquiatria, Santiago, Chile Peking Univ, Hlth Sci Ctr, George Inst Global Hlth, Beijing, Peoples R China Australian Catholic Univ, Nursing Res Inst, St Vincents Hlth Australia Sydney, Sydney, NSW, Australia Univ Cent Lancashire, Fac Hlth & Wellbeing, Preston, Lancs, England Univ Chile, Fac Med, Dept Ciencias Neurol, Santiago, Chile Univ Sao Paulo, Ribeirao Preto Med Sch, Stroke Serv Neurol Div, Ribeirao Preto, Brazil Fukuoka Univ, Fac Med, Dept Prevent Med & Publ Hlth, Fukuoka, Fukuoka, Japan Univ Leicester, Dept Cardiovasc Sci, Leicester Biomed Res Ctr, Leicester, Leics, England Univ Leicester, Natl Inst Hlth Res, Leicester Biomed Res Ctr, Leicester, Leics, England Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland George Inst Global Hlth, Sydney, NSW, Australia Univ Desarrollo, Serv Neurol, Dept Neurol & Psiquiatria Clin Alemana Santiago, Santiago, Chile St Vincents Hlth Australia Sydney, Sydney, NSW, Australia Australian Catholic Univ, Sydney, NSW, Australia Univ Cent Lancashire, Stroke Practice Res Unit, Sch Hlth, Lancashire Clin Trials Unit, Preston, Lancs, England Univ Leicester, Dept Cardiovasc Sci, Cardiovasc Res Ctr, British Heart Fdn, Leicester, Leics, England Univ Kelaniya, Dept Pharmacol, Fac Med, Colombo, Sri Lanka Christian Med Coll & Hosp, Dept Neurol, Ludhiana, India Kaohsiung Med Univ & Hosp, Dept Neurol, Kaohsiung, Taiwan Linkou Chang Gung Mem Hosp, Dept Neurol, Taipei, Taiwan Peking Union Med Coll Hosp, Beijing, Peoples R China Univ Sao Paulo, Ribeirao Preto Sch Med, Ribeirao Preto, Brazil Monash Univ, Dept Epidemiol & Prevent Med, Melbourne, Vic, Australia Univ Cent Lancashire, Sch Hlth Sci, Coll Hlth & Wellbeing, Preston, Lancs, England Univ Desarrollo, Santiago, Chile Univ New South Wales, Neurosci Res Australia, Sydney, NSW, Australia Natl Univ Singapore, Dept Pharmacol, Singapore, Singapore Bradford Royal Infirm, Bradford Inst Hlth Res, Leeds, W Yorkshire, England Christian Med College, Ludhiana, Punjab, India RemediumOne Pvt Ltd, Kandy, Sri Lanka Kaohsiung Med Univ, Chung Ho Mem Hosp, Kaohsiung, Taiwan Calvary Publ Hosp Bruce, Bruce, Australia Royal North Shore Hosp, St Leonards, NSW, Australia Royal Prince Alfred Hosp, Camperdown, NSW, Australia Concord Repatriat Gen Hosp, Camperdown, NSW, Australia Fiona Stanley Hosp, Camperdown, NSW, Australia Macquarie Base Hosp, Melbourne, Vic, Australia Univ Sao Paulo, Fac Med Ribeirao Preto, Hosp Clin, Sao Paulo, Brazil Hosp Governador Celso Ramos, Florianopolis, SC, Brazil Sao Paulo State Univ, Hosp Fac Med Botucatu, UNESP, Sao Paulo, Brazil Yangquan Coalmine Grp Gen Hosp, Yangquan, Peoples R China Nanjing Med Univ, Nanjing Hosp 1, Nanjing, Jiangsu, Peoples R China 85 Hosp Peoples Liberat Army, Beijing, Peoples R China Chifeng Univ, Affiliated Hosp, Chifeng, Peoples R China Beijing Pinggu Hosp, Beijing, Peoples R China Wenzhou Med Univ, Affiliated Hosp 1, Wenzhou, Peoples R China Soochow Univ, Affiliated Hosp 2, Suzhou, Peoples R China Hebei Med Univ, Hosp 3, Shijiazhuang, Hebei, Peoples R China Capital Med Univ, Xuanwu Hosp, Beijing, Peoples R China Jining Med Univ, Affiliated Hosp, Jining, Peoples R China Third Peoples Hosp Huizhou, Huizhou, Peoples R China Second Cangzhou Cent Hosp, Cangzhou, Peoples R China Shanghai Jiao Tong Univ, Hosp Affiliated, Sch Med, Shanghai, Peoples R China Baogang Hosp, Baotou, Peoples R China Harbin Med Univ, Affiliated Hosp 1, Harbin, Heilongjiang, Peoples R China Shanghai Jiao Tong Univ Sch, Tong Ren Hosp, Peoples Hosp Hejian City, Shanghai, Peoples R China Peking Univ, Shougang Hosp, Beijing, Peoples R China Guangzhou Med Univ, Affiliated Hosp 3, Guangzhou, Guangdong, Peoples R China Second Hosp Nanchang, Nanchang, Jiangxi, Peoples R China Bethune Int Peace Hosp, Beijing, Peoples R China Hua Henan Prov Peoples Hosp, Beijing, Peoples R China Hua Henan Prov Peoples Hosp, Zhengzhou, Henan, Peoples R China Shanghai Jiao Tong Univ, Sch Med, Shanghai Ninth Peoples Hosp, Shanghai, Peoples R China Shijiazhuang Cent Hosp, Shijiazhuang, Hebei, Peoples R China Hosp Base San Jos de Osorno, Osorno, Chile Christian Med Coll & Hosp, Ludhiana, Punjab, India Unit Narayana Hrudayalaya Ltd, Mazumdar Shaw Med Ctr, Bangalore, Karnataka, India Dr Ramesh Cardiac & Multispecial Hosp Pvt Ltd, Guntur, India Post Grad Inst Med Educ & Res, Chandigarh, India Baby Mem Hosp Ltd, Calicut, Kerala, India Sree Chitra Tirunal Inst Med Sci & Technol, Thiruvananthapuram, Kerala, India Sri Jayawardenepura Gen Hosp, Sri Jayawardenepura Kott, Sri Lanka Colombo North Teaching Hosp, Colombo, Sri Lanka Colombo South Coching Hosp, Colombo, Sri Lanka Linkou Chang Gung Mem Hosp, Taoyuan, Taiwan Taipei Med Univ, Shuang Ho Hosp, Taipei, Taiwan En Chu Kong Hosp, New Taipei, Taiwan Natl Cheng Kung Univ Hosp, Tainan, Taiwan Queen Alexandra Hosp, Portsmouth, Hants, England Portsmouth Hosp NHS Natl Hlth Serv iTrust, Portsmouth, Hants, England Univ Coll London Hosp NHS Fdn Trust, London, England Univ Hosp Birmingham NHS Fdn Trust, Queen Elizabeth Hosp Birmingham, Birmingham, W Midlands, England Southend Univ Hosp NHS Fdn Trust, Southend On Sea, England Kings Coll Hosp London, London, England York Teaching Hosp NHS Fdn Trust, York, N Yorkshire, England Nottingham Univ Hosp NHS Trust, Nottingham, England Blackpool Teaching Hosp NHS Fdn Trust, Blackpool, England Gloucestershire Hosp NHS Fdn Trust, Gloucestershire Royal Hosp, Gloucester, England Teaching Hospi NHS Fdn Trust, London, England Royal Cornwall Hosp NHS Trust, Truro, England Royal London Hosp, Barts Hlth NHS Trust, London, England Sheffield Teaching Hosp NHS Fdn Trust, Sheffield, S Yorkshire, England Cambridge Univ Hosp NHS Fdn Trust, Addenbrookes Hosp, Cambridge, England Royal Victoria Hosp, Belfast Hlth & Social Care Trust, London, England Pinderfields Gen Hosp, Mid Yorkshire Hosp NHS Trust, Wakefield, England Royal Devon & Exeter NHS Fdn Trust, London, England Bradford Teaching Hosp NHS Fdn Trust, Bradford, W Yorkshire, England Great Western Hosp NHS Fdn Trust, Swindon, Wilts, England Watford Dist Gen Hosp, Watford, England Imperial Coll Healthcare NHS Trust, London, England Medway NHS Fdn Trust, Gillingham, England Royal Liverpool & Broadgreen Univ NHS Trust, Liverpool, Merseyside, England Calderdale & Huddersfield NHS Fdn Trust, Huddersfield, W Yorkshire, England Hywel Dda Univ Hlth Board, Haverfordwest, Wales Chesterfield Royal Hosp NHS Fdn Trust, Calow, England Luton & Dunstable Univ Hosp NHS Fdn Trust, Luton, Beds, England Countess Chester Hosp NHS Fdn Trust, Chester, Cheshire, England Peterborough City Hosp, Peterborough, Cambs, England Univ Hosp Leicester NHS Trust, Leicester Royal Infirm, Leicester, Leics, England Dist Hosp NHS Fdn Trust, London, England Barnsley Hosp NHS Fdn Trust, Barnsley, England Dorset Cty Hosp NHS Fdn Trust, Dorchester, England Royal Bournemouth & Christchurch Hosp NHS Fdn Tru, Royal Bournemouth Hosp, Bournemouth, Dorset, England Southern Hlth & Social Care Trust, Craigavon Area Hosp, Portadown, England United Lincolnshire Hosp NHS Trust, Pilgrim Hosp, Lincoln, England Bedford Hosp NHS Trust, Bedford, England Sao Paulo State Univ, Hosp Fac Med Botucatu, UNESP, Sao Paulo, Brazil National Health and Medical Research Council of Australia: 1066966

Summary Background The ELIANA trial showed that 61 (81%) of 75 paediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia achieved overall remission after treatment with tisagenlecleucel, a chimeric antigen receptor targeted against the CD19 antigen. We aimed to evaluate patient-reported quality of life in these patients before and after tisagenlecleucel infusion. Methods ELIANA, a global, single-arm, open-label, phase 2 trial, was done in 25 hospitals across Australia, Austria, Belgium, Canada, France, Germany, Italy, Japan, Norway, Spain, and the USA. Patients with B-cell acute lymphoblastic leukaemia aged at least 3 years at the time of screening and 21 years or younger at the time of initial diagnosis who were in second or greater bone marrow relapse, chemorefractory, relapsed after allogeneic stem-cell transplantation, or were otherwise ineligible for allogeneic stem-cell transplantation were enrolled. Patients received a single intravenous administration of a target dose of 0·2–5 × 106 transduced viable T cells per kg for patients weighing 50 kg or less or 0·1–2·5 × 108 transduced viable T cells for patients weighing more than 50 kg. The primary outcome, reported previously, was the proportion of patients who achieved remission. A prespecified secondary endpoint, reported here, was patient-reported quality of life measured with the Pediatric Quality of Life Inventory (PedsQL) and European Quality of Life-5 Dimensions questionnaire (EQ-5D). Patients completed the questionnaires at baseline, day 28, and months 3, 6, 9, and 12 after treatment. The data collected were summarised using descriptive statistics and post-hoc mixed models for repeated measures. Change from baseline response profiles were illustrated with cumulative distribution function plots. The proportion of patients achieving the minimal clinically important difference and normative mean value were reported. Analysis was per protocol. This study is registered with ClinicalTrials.gov , NCT02435849 . Findings Between April 8, 2015, and April 25, 2017, 107 patients were screened, 92 were enrolled, and 75 received tisagenlecleucel. 58 patients aged 8–23 years were included in the analysis of quality of life. At baseline, 50 (86%) patients had completed the PedsQL questionnaire and 48 (83%) had completed the EQ-5D VAS. Improvements in patient-reported quality-of-life scores were observed for all measures at month 3 after tisagenlecleucel infusion (mean change from baseline to month 3 was 13·3 [95% CI 8·9–17·6] for the PedsQL total score and 16·8 [9·4–24·3] for the EQ-5D visual analogue scale). 30 (81%) of 37 patients achieved the minimal clinically important difference at month 3 for the PedsQL total score and 24 (67%) of 36 patients achieved this for the EQ-5D visual analogue scale. Interpretation These findings, along with the activity and safety results of ELIANA, suggest a favourable benefit–risk profile of tisagenlecleucel in the treatment of paediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia. Funding Novartis.

The mammalian mono-&alpha, 2,8-sialyltransferase ST8Sia VI has been shown to catalyze the transfer of a unique sialic acid residues onto core 1 O-glycans leading to the formation of di-sialylated O-glycosylproteins and to a lesser extent to diSia motifs onto glycolipids like GD1a. Previous studies also reported the identification of an orthologue of the ST8SIA6 gene in the zebrafish genome. Trying to get insights into the biosynthesis and function of the oligo-sialylated glycoproteins during zebrafish development, we cloned and studied this fish &alpha, 2,8-sialyltransferase homologue. In situ hybridization experiments demonstrate that expression of this gene is always detectable during zebrafish development both in the central nervous system and in non-neuronal tissues. Intriguingly, using biochemical approaches and the newly developed in vitro MicroPlate Sialyltransferase Assay (MPSA), we found that the zebrafish recombinant enzyme does not synthetize diSia motifs on glycoproteins or glycolipids as the human homologue does. Using comparative genomics and molecular phylogeny approaches, we show in this work that the human ST8Sia VI orthologue has disappeared in the ray-finned fish and that the homologue described in fish correspond to a new subfamily of &alpha, 2,8-sialyltransferase named ST8Sia VIII that was not maintained in Chondrichtyes and Sarcopterygii.

To investigate the inducing effect of down-regulation of MCL-1 by diallyl disulfide(DADS) on the GCCK-8 was used to detect the effect of DADS on proliferation of K562 cells, flow cytometry was employed to observe the effect of cycle arrest by DADS and RNAi silencing MCL-1 gene in K562 cells. The expressions of MCL-1, PCNA and CDK1 in K562 cells treated with DADS were detected by Western blot. The amphigamy of MCL-1 with PCNA and CDK1 was detected by Coimmunoprecipitation.CCK-8 detection showed that the inhibition rates of K562 cells treated with 15, 30, 60, 120, 240 µmol/L DADS were 32.48%, 59.34%, 66.42%, 77.06%, 81.05% respectively (P0.05). Flow cytometry analysis revealed that the perecentages of GDADS can inhibit the K562 cell proliferation and induce them arrest G

Rationale: Displaced olecranon fracture is a common injury following a fall or direct trauma to the elbow. There have been no reports of patients with a displaced olecranon fracture who have only received nonoperative manipulative reduction with Chinese herbs. Patient concerns: The patient was a 64-year-old woman with a complex elbow injury that occurred in a traffic accident. The patient complained of severe, painful limitation of motion on straightening or bending. Diagnoses: The patient was diagnosed with a displaced fracture of the left olecranon (type IIA olecranon fracture according to the Mayo classification system). Interventions: The patient underwent nonoperative manipulation with Chinese herbs. Outcomes: The fracture was successfully reduced. After 3 to 4 months of follow-up, severe pain and disability in the elbow were improved following reduction of the left olecranon fracture in which there was no longer a displacement. Lessons: Nonoperative manipulative reduction performed by a well-trained physician with Chinese herbs may be a treatment option for displaced olecranon fractures.

Radiation is a form of energy derived from a source that is propagated through material in space. It consists of ionizing radiation or nonionizing radiation. Ionizing radiation is a feature of the environment and an important tool in medical treatment, but it can cause serious damage to organisms. A number of protective measures and standards of protection have been proposed to protect against radiation. There is also a need for biomarkers to rapidly assess individual doses of radiation, which can not only estimate the dose of radiation but also determine its effects on health. Proteomics, genomics, metabolomics, and lipidomics have been widely used in the search for such biomarkers. These topics are discussed in depth in this review.

Calreticulin (CRT) is an endoplasmic reticulum luminal calcium-binding protein with multiple cellular functions, including intracellular Ca2+ homeostasis, oxidative stress responses, and lectin binding. CRT can also modulate cell adhesion, cell-cell interactions, migration, phagocytosis, integrin-dependent Ca2+ signaling, and immune responses, and plays an important role in cellular proliferation, differentiation, and apoptosis. Given these roles, it is not surprising that CRT function has important implications in health and disease. Considerable evidence in recent years suggests that CRT dysfunction is associated with cancer and that CRT could be a diagnostic marker and a target for cancer therapy. These topics are discussed in depth in this review.

To study the clinical efficacy of amphotericin B and voriconazole in the treatment of invasive fungal infection in children with acute lymphoblastic leukemia(ALL) during chemotherapy.The clinical data of 214 patients with acute lymphoblastic leukemia admitted in our hospital from March 2014 to February 2017 was retrospectively analyzed. Among them 65 patients had invasive fungal infection (IFI) during the chemotherapy period, out of them 35 patients treated with voriconazole were enrolled in group A; anather 30 patients treated with amphotericin B were enrolled in group B. The clinical factors that affected the incidence of IFI was statistically analyzed. And the efficacy and adverse reactions in children with ALL were compared after treatment for 8 weeks.The incidence of IFI in children with ALL in this study was 30.37%, and was related with the duration of hospitalization and the level of neutrophil deficiency (P0.05). The total effective rates of group A and group B were 72.28% and 43.33%, respectively, their difference was statistically significant between 2 group (P0.05). The incidence of renal function impairment, digestive dysfunction and neurotoxicity were 8.57%, 5.71% and 5.71% in children with ALL treated with voriconazole respectively, which were lower than those in children treated with amphotericin B (P0.05). The score index of Physical health, energy state, emotion control and overall health in group A were significantly higher than those in B group, and the difference was statistically significant (P0.05).The occurrence of IFI in children with ALL relats with the time of hospitalization and the level of neutrophils. The clinical effect of voriconazole is better, and the incidence of adverse reactions can be reduced, suggesting important clinical significance.

Targeting KRAS and MYC has been a tremendous challenge in cancer drug development. Genetic studies in mouse models have validated the efficacy of silencing expression of both KRAS and MYC in mutant KRAS driven tumors. We investigated the therapeutic potential of a new oligonucleotide-mediated gene silencing technology (U1 Adaptor) targeting KRAS and MYC in pancreatic cancer. Nanoparticles in complex with anti-KRAS U1 Adaptors (U1-KRAS) showed remarkable inhibition of KRAS in different human pancreatic cancer cell lines in vitro and in vivo. As a nanoparticle-free approach is far easier to develop into a drug, we refined the formulation of U1 Adaptors by conjugating them to tumor targeting peptides (iRGD and cRGD). Peptides coupled to fluorescently tagged U1 Adaptors showed selective tumor localization in vivo. Efficacy experiments in pancreatic cancer xenograft models showed highly potent (>90%) anti-tumor activity of both iRGD and (cRGD)2-KRAS Adaptors. U1 Adaptors targeting MYC inhibited pancreatic cancer cell proliferation caused apoptosis in vitro (40–70%) and tumor regressions in vivo. Comparison of iRGD conjugated U1 KRAS and U1 MYC Adaptors in vivo revealed a significantly greater degree of cleaved caspase-3 staining and decreased Ki67 staining as compared with controls. There was no significant difference in efficacy between the U1 KRAS and U1 MYC Adaptor groups. Our results validate the value in targeting both KRAS and MYC in pancreatic cancer therapeutics and provide evidence that the U1 Adaptor technology can be successfully translated using a nanoparticle free delivery system to target two undruggable genes in cancer.

Ellagitannins is a kind of phenolic compounds with many biological activities. Recent studies have found that the effective ingredients of these compounds have close relationship with their colon-derived bacteria metabolites, that is urolithins. The objective of this study was to review the structure characteristics, types and distribution of urolithins, improvement in diseases related to prostate, breast and colon, as well as anti-cancer, anti-oxidation, anti-inflammation and other biological activities. The present review will lay the foundation for development and utilization of urolithins.

To analyze the complications and nursing countermeasures of PICC (Peripherally Inserted Central Catheter) catheters using children PICC catheter technique 40 cases, complications were observed, and analyze the original causes, in order to propose a solution. There were 10 cases of catheter blockage, 5 cases of catheter infection, 6 cases of phlebitis, 5 cases of puncture difficulties, 2 cases of poor feeding tube, 2 cases of bleeding puncture site with the continuous exploration and research of nursing intervention, the production of clinical complications from PICC has been used in children were greatly reduced.

The p53 protein ensures cellular fidelity by suppressing or killing cells under stresses that enhance the mutation rate. Evidence suggests that the p53 protein may also ensure the fidelity of the epigenome. In this study a group of drugs that alter the deoxycytosine methylation patterns in cellular DNA are shown to preferentially kill human and mouse cells that contain p53 mutations or deficiencies. These observations are extended to mice that contain p53 deficiencies or missense mutations in their genome, which are preferentially killed when compared to mice with a wild type p53 gene. This is also the case for human cancer cell xenografts containing p53 mutations, which preferentially are killed by these drugs when compared to similar tumors with wild type p53. The loss of p53 function enhances a synthetic lethality with drugs that block or alter the patterns of deoxycytidine methylation in the genome.

The inactivation of p53 functions enhances the efficiency and decreases the latency of producing induced pluripotent stem cells (iPSC) in culture. The formation of iPSCs in culture starts with a rapid set of cell divisions followed by an epigenetic reprogramming of the DNA and chromatin. The mechanisms by which the p53 protein inhibits the formation of iPSCs are largely unknown. Using a temperature sensitive mutant of the p53 (Trp53) gene, we examined the impact of the temporal expression of wild type p53 in preventing stem cell induction from somatic cells. We also explored how different p53 mutant alleles affect the reprogramming process. We found that little or no p53 activity favors the entire process of somatic cell reprogramming. Reactivation of p53 at any time point during the reprogramming process not only interrupted the formation of iPSCs, but also induced newly formed stem cells to differentiate. Among p53-regulated genes, p21 (Cdkn1a), but not Puma (Bbc3) played a partial role in iPSCs formation probably by slowing cell division. Activation of p53 functions in iPSCs induced senescence and differentiation in stem cell populations. High rate of birth defects and increases in DNA methylation at the IGF2-H19 loci in female offspring of p53 knockout mice suggested that the absence of p53 may give rise to epigenetic instability in a stochastic fashion. Consistently, selected p53 missense mutations showed differential effects on the stem cell reprogramming efficiency in a c-Myc dependent manner. The absence of p53 activity and functions also contributed to an enhanced efficiency of iPSC production from cancer cells. The production of iPSCs in culture from normal and cancer cells, although different from each other in several ways, both responded to the inhibition of reprogramming by the p53 protein. Cancer Res; 72(21); 5635–45. ©2012 AACR.

Considerable evidence in recent years suggests that garlic has anti-proliferative effects against various types of cancer. Garlic contains water-soluble and oil-soluble sulfur compounds. Oil-soluble compounds such as diallyl sulfide (DAS), diallyl disulfide (DADS), diallyl trisulfide (DATS) and ajoene are more effective than water-soluble compounds in protection against cancer. DADS, a major organosulfur compound derived from garlic, can decrease carcinogen-induced cancers in experimental animals and inhibit the proliferation of various types of cancer cells. Its mechanisms of action include: the activation of metabolizing enzymes that detoxify carcinogens; suppression of the formation of DNA adducts; antioxidant effects; regulation of cell-cycle arrest; induction of apoptosis and differentiation; histone modification; and inhibition of angiogenesis and invasion. These topics are discussed in depth in this review.

We reported a 2-year-old boy with developmental delay, mild mental retardation, and severe craniofacial malformation, including facial asymmetry with hypoplasia of the left zygoma, maxilla, and mandible, and left anophthalmia and anotia. A genome-wide screen revealed a 1.38 Mb duplication on chromosome 1q31.1, which was absent in his parents and 27 healthy controls. The duplication region contains two Refseq genes, PLA2G4A and C1orf99, which have not been reported to be implicated in craniofacial malformation. Functional studies of these genes and additional clinical analysis are necessary to elucidate the pathogenesis of craniofacial malformation.

Diallyl disulfide (DADS) has shown potential as a therapeutic agent in various cancers. Previously, we found that myeloid cell leukemia sequence 1 (Mcl1) was downregulated in DADS-induced cell cycle arrest in HL-60 human leukemia cells. Here, we investigated the role of this protein in DADS-induced G2/M cell cycle arrest in HL-60 cells. We demonstrated that DADS treatment significantly increased the proportion of G2/M phase HL-60 cells (P

This work presents a simple, low-cost and reusable label-free method for detecting protein tyrosine kinase activity using a tyrosinase-based amperometric biosensor (tyrosine kinase biosensor). This method is based on the observation that phosphorylation can block the tyrosinase-catalyzed oxidation of tyrosine or tyrosyl residue in peptides. Therefore, the activity of p60c-src protein tyrosine kinase (Src) on the developed tyrosine kinase biosensor could be quickly determined when its specific peptide substrate, p60c-src substrate I, was used. The tyrosine kinase biosensor was highly sensitive to the activity of Src with a linear dynamic range of 1.9-237.6 U/mL and the lowest detection limit of 0.23 U/mL. Interestingly, the tyrosine kinase activity can be measured using the developed tyrosine kinase biosensor repetitively without regeneration. The inhibitory effect of various kinase inhibitors on the Src activity could be determined on the tyrosine kinase biosensor. Src-specific inhibitors, PP2 and Src inhibitor I, effectively suppressed Src activity, whereas PD153035, an inhibitor of the epidermal growth factor receptor, was ineffective. Staurosporine, a universal kinase inhibitor, inhibited Src activity in an ATP concentration-dependent manner. These results suggests that the activities of tyrosine kinases and their behaviors toward various reagents can be effectively measured using the developed tyrosine kinase biosensor.

Human fertilization begins when spermatozoa bind to the extracellular matrix coating of the oocyte, known as the zona pellucida (ZP). One spermatozoan then penetrates this matrix and fuses with the egg cell, generating a zygote. Although carbohydrate sequences on the ZP have been implicated in sperm binding, the nature of the ligand was unknown. Here, ultrasensitive mass spectrometric analyses revealed that the sialyl-Lewis(x) sequence [NeuAcα2-3Galβ1-4(Fucα1-3)GlcNAc], a well-known selectin ligand, is the most abundant terminal sequence on the N- and O-glycans of human ZP. Sperm-ZP binding was largely inhibited by glycoconjugates terminated with sialyl-Lewis(x) sequences or by antibodies directed against this sequence. Thus, the sialyl-Lewis(x) sequence represents the major carbohydrate ligand for human sperm-egg binding.

Diallyl disulfide (DADS) is a chemopreventive agent that can induce apoptosis in many tumor cells. Reactive oxygen species (ROS) are important mediators in apoptosis induced by various stimuli, including chemopreventive agents. The phosphotransferase c-JUN N-terminal kinase (JNK) has been shown to regulate apoptosis. In this study, we found that DADS-induced apoptosis in human leukemia HL-60 cells is mediated by ROS-activated JNK. The DADS-treated HL-60 cells showed a dose- and time-dependent decrease in cell viability and proliferation. Agarose gel electrophoresis of cells treated with 10.0 or 20.0 mg/L DADS for 24 h showed a characteristic ladder pattern in their DNA. Levels of DADS-induced ROS, as measured by 2',7'-dichlorofluorescein diacetate (DCFH-DA) fluorescence, also showed dose- and time-dependent increases in HL-60 cells. Activity of JNK was induced by DADS in a dose-dependent manner; HL-60 cells exposed to 10.0 mg/L DADS for 8 h showed maximum levels of phosphorylated JNK, which decreased when exposed for additional 4h. In contrast, Sp600125, a specific inhibitor of JNK, blocked apoptosis of HL-60 cells exposed to DADS. N-Acetylcysteine (NAC), a known antioxidant, also decreased ROS generation, effectively blocked apoptosis, and decreased DADS-induced phosphorylated JNK levels. These results suggest that JNK is involved in DADS-induced ROS-mediated apoptosis in HL-60 cells.

1. Diallyl disulphide (DADS) has potential as a chemopreventive and therapeutic agent. Previous studies have reported that Ras-related C3 botulinum toxin substrate 2 (Rac2), a regulatory subunit of the NADPH oxidase complex, is upregulated in DADS-induced apoptosis in human leukaemia HL-60 cells. The aim of the present study was to investigate the role of Rac2, NADPH oxidase and reactive oxygen species (ROS) in DADS-induced apoptosis. 2. Expression of the Rac2 gene along with that of five other genes of NADPH oxidase subunits were in HL-60 cells measured by Sybergreen quantitative real-time polymerase chain reaction. RNA interference was used to test the effect of Rac2. Protein expression was evaluated using western blot analysis and ROS levels were measured by 2',7'-dichlorofluorescein diacetate (DCFH-DA) fluorescence. DNA fragmentation and flow cytometry analysis were used to detect apoptotic cells. 3. Levels of Rac2 gene and protein were significantly upregulated and NADPH oxidase was activated in DADS-induced apoptosis. Pretreatment of HL-60 cells with small interfering (si) RNAs to inhibit Rac2 blocked DADS-induced apoptosis. Diallyl disulphide-induced intracellular ROS production was increased in phorbol myristate acetate-stimulated cells, but decreased in Rac2 siRNA-treated cells. In Rac2 siRNA-treated cells, activator protein-1 and caspase 3 levels decreased, c-myc protein levels were increased and p38 protein levels were unchanged compared with Rac2-competent, DADS-treated cells. 4. These results demonstrate that NADPH oxidase is the main source of DADS-induced ROS. In addition, Rac2 selectively activates the c-Jun N-terminal kinase pathway, but not the p38 pathway, in DADS-induced apoptosis. So, Rac2, NADPH oxidase and ROS have a critical role in DADS-induced apoptosis in human leukaemia HL-60 cells.