Targeting JWA for Cancer Therapy: Functions, Mechanisms and Drug Discovery

Tumor heterogeneity limits the precision treatment of targeted drugs. It is important to find new tumor targets. JWA, also known as ADP ribosylation factor-like GTPase 6 interacting protein 5 (ARL6IP5, GenBank: AF070523, 1998), is a microtubule-associated protein and an environmental response gene. Substantial evidence shows that JWA is low expressed in a variety of malignancies and is correlated with overall survival. As a tumor suppressor, JWA inhibits tumor progression by suppressing multiple oncogenes or activating tumor suppressor genes. Low levels of JWA expression in tumors have been reported to be associated with multiple aspects of cancer progression, including angiogenesis, proliferation, apoptosis, metastasis, and chemotherapy resistance. In this review, we will discuss the structure and biological functions of JWA in tumors, examine the potential therapeutic strategies for targeting JWA and explore the directions for future investigation

Fitting characteristics of N95 filtering-facepiece respirators used widely in China.

BACKGROUND: Millions of people rely on N95 filtering facepiece respirators to reduce the risk of airborne particles and prevent them from respiratory infections. However, there are no respirator fit testing and training regulations in China. Meanwhile, no study has been conducted to investigate the fit of various respirators. The objective of this study was to investigate whether people obtained adequate fit when wearing N95 filtering facepiece respirators (FFRs) used widely in China. METHODS: Fifty adult participants selected using the Chinese respirator fit test panel donned 10 common models of N95 FFRs. Fit factors (FF) and inward leakage were measured using the TSI PortaCount Plus. Each subject was tested with three replications for each model. A subject was considered to pass the fit test when at least two of the three FFs were greater than 100. Two models were conducted fit tests before and after training to assess the role of training. RESULTS: The geometric mean FFs for each model and trained subjects ranged from <10 to 74.0. The fifth percentile FFs for only two individual respirator models were greater than 10 which is the expected level of performance for FFRs. The passing rates for these two models of FFRs were 44.7% and 20.0%. The passing rates were less than 10.0% for the other eight models. There were 27 (54%) participants who passed none of the 10 FFRs. The geometric mean FFs for both models when the subjects received training (49.7 and 74.0) were significantly larger than those when the same group of subjects did not receive any training (29.0 and 30.9) (P<0.05). CONCLUSIONS: FFRs used widely in China should be improved according to Chinese facial dimensions. Respirator users could benefit from respirator training and fit testing before using respirators

Self DNA from Lymphocytes That Have Undergone Activation-Induced Cell Death Enhances Murine B Cell Proliferation and Antibody Production

<div><p>Systemic lupus erythematosus (SLE) is characterized by prominent autoinflammatory tissue damage associated with impaired removal of dying cells and DNA. Self DNA-containing immune complexes are able to activate both innate and adaptive immune responses and play an important role in the maintenance and exacerbation of autoimmunity in SLE. In this study, we used DNA from lymphocytes that have undergone activation-induced cell death (ALD-DNA) and analyzed its role on the activation and differentiation of B cells from normal BALB/c mice as well as lupus-prone MRL^+/+ and MRL/lpr mice. We found that ALD-DNA directly increased the expression of costimulatory molecules and the survival of naïve B cells <i>in vitro</i>. Although ALD-DNA alone had little effect on the proliferation of naïve B cells, it enhanced LPS-activated B cell proliferation <i>in vitro</i> and <i>in vivo</i>. In addition, ALD-DNA increased plasma cell numbers and IgG production in LPS-stimulated cultures of naïve B cells, in part via enhancing IL-6 production. Importantly, B cells from lupus mice were hyperresponsive to ALD-DNA and/or LPS relative to normal control B cells in terminal plasma cell differentiation, as evidenced by increases in CD138⁺ cell numbers, IgM production, and mRNA levels of B lymphocyte-induced maturation protein-1 (Blimp-1) and the X-box binding protein 1 (XBP1). Furthermore, ALD-DNA enhanced CD40-activated naïve B cell proliferation. Collectively, these data indicate that self DNA can serve as a DAMP (damage-associated molecular pattern) that cooperates with signals from both innate and adaptive immunity to promote polyclonal B cell activation, a common characteristic of autoimmune diseases.</p></div

Enhancement of CD40-stimulated naïve B cell proliferation by ALD-DNA.

<p>(<b>A</b>) Naïve B cells were pre-incubated for 20 min with polymyxin B (PMB; 20 µg/ml) before the addition of ALD-DNA (50 µg/ml), LPS (100 ng/ml), anti-CD40 (1 µg/ml), LPS (100 ng/ml) plus ALD-DNA (50 µg/ml), or anti-CD40 (1 µg/ml) plus ALD-DNA (50 µg/ml). After 72 h stimulation, cell proliferation was detected by performing BrdU incorporation assay using ELISA. Data are presented as the means ±SEM of three independent experiments. (<b>B</b>) CFSE-labeled naïve B cells were cultured in media containing ALD-DNA, anti-CD40, or both (at the concentrations as described above) for 72 h. Cell division was monitored by measuring the dilution of CFSE. Shaded areas show the cell division peaks predicted by the ModFit software. Results from one representative experiment of three are shown. **<i>P</i><0.01.</p

Synergistic enhancement of LPS-driven IgG production in naive B cells by ALD-DNA stimulation.

<p>Naive B cells were cultured for 6 days in media containing ALD-DNA (50 µg/ml) with or without LPS (100 ng/ml). Cell culture supernatants were collected, and the levels of IgM and IgG were measured by ELISA. Bars represent the means ±SEM of three independent experiments (n = 5). ND (not detected). **<i>P</i><0.01.</p

Up-regulation of CD86 and MHC class II expression in naïve B cells by ALD-DNA stimulation.

<p>(<b>A</b>) Naïve B cells were incubated with ALD-DNA (50 µg/ml) in the presence or absence of LPS ranging from 0.01 µg/mL to 10 µg/ml for 72 h. The numbers of CD86-expressing B cells after each treatment were determined by flow cytometry. (<b>B</b>) Naive B cells were stimulated with ALD-DNA or <i>E. coli</i> single-stranded (ss) DNA (both at 50 µg/ml) for 72 h. CD86 and MHC class II expression was determined by performing flow cytometry. Histogram plots show the mean fluorescence intensity (MFI) of these surface molecules. The data are representative of three independent experiments.</p

Promotion of plasma cell differentiation and Ig production in lupus B cells by ALD-DNA.

<p>Splenic B cells from 16- to 20-week-old MRL/lpr mice and 12-week-old MRL^+/+ mice were cultured in media alone, or in the presence of ALD-DNA (50 µg/ml), LPS (100 ng/ml), or both for different periods as indicated below. (<b>A</b>) After 72 h stimulation, viable cells were analyzed for B220 and CD138 surface expression by flow cytometry. Representative dot plots showed the frequencies of plasmablasts (B220⁺CD138^hi, lower panels, MRL/lpr, n = 6) or plasma cells (B220⁻CD138⁺, upper panels, MRL^+/+, n = 6) generated after each treatment. (<b>B</b>) Expression of Blimp-1 and XBP1 mRNA from lupus B cells cultured for 96 h was examined by real-time PCR. Results are expressed as the fold induction of gene transcription relative to their untreated controls (means ±SEM, n = 6). (<b>C</b>) Ig production in cell culture supernatants harvested on day 6 was determined by ELISA. Bars represent the means ±SEM of three independent experiments (n = 6). *<i>P</i><0.05, **<i>P</i><0.01.</p

Effect of ALD-DNA on CD138, Blimp-1, XBP1, and IL-6 expression in naïve B cells.

<p>Naïve B cells were cultured in media containing ALD-DNA (50 µg/ml), LPS (100 ng/ml), or both for different periods as described below. (<b>A</b>) After 72 h stimulation, Cells were analyzed for B220 and CD138 surface expression by flow cytometry. The number indicates the percentage of B220⁻CD138⁺ cells in the gate. Similar results were obtained in three independent experiments. (<b>B</b>) Expression of Blimp-1 and XBP1 mRNA from B cells cultured for 96 hours was examined by real-time PCR. Fold induction relative to their untreated controls is shown (means ±SEM, n = 5). (<b>C</b>) Expression of IL-6 mRNA in B cells after 6 h stimulation was examined by real-time PCR. Fold induction relative to their untreated controls is shown (means ±SEM, n = 5); The amounts of IL-6 protein in the culture supernatants of B cells after 72 h stimulation were measured by ELISA (n = 6, a line linked two dots represents a pair observation). Up-regulation of IL-6 protein was undetectable in all samples after ALD-DNA treatment. *<i>P</i><0.05 as compared to the LPS, ***<i>P</i><0.001 as compared to the LPS.</p

Nonclassical crystallization of variable valency metal in the biomineralization process

In nature, microorganisms can coexist and interact with various metals and their metallic compounds, ultimately affecting their migration rate, circulation process, and distribution state in the environment, which confirms that they can participate in every step of the metal geochemical cycle. As the most active and powerful geological force in the earth’s surface biosphere, the biological action will inevitably have a great influence on the formation and transformation of sedimentary lithosphere minerals. Of which, biomineralization refers to the process by which living forms influence the precipitation of minerals. The microorganisms concentrate aqueous dissolved metals onto cell walls and at intracellular sites during the life cycle and strongly bind metals during early diagenesis. For this process, nonclassical crystals are disequilibrium assemblages, which are created and maintained during life by dynamic metabolism. The biomineralization can be interpreted as an important medium for microbial-mineral-environmental interactions. This chapter mainly reviews nonclassical crystallization behaviors occurring in the biomineralization processes of variable valency cations (As, Cr, Fe, Mn, and U). The nonclassical crystallization behaviors of variable valency cations (As, Cr, Fe, and Mn) for biomineralization and the nonclassical crystallization behaviors in the biomineralization processes with U by plants and microbes are discussed