Emerging activated tungsten dust: Source, environmental behaviors, and health effects.

Fusion energy investigation has stepped to a new stage adopting deuterium and tritium as fuels from the previous stage concentrating hydrogen plasma physics. Special radiation safety issues would be introduced during this stage. In addition to industrial and military uses, tungsten is also regarded as the most promising plasma facing material for fusion reactors. During the operation of fusion reactors, tungsten-based plasma facing materials can be activated via neutron nuclear reaction. Meanwhile, activated tungsten dust can be produced when high-energy plasma interacts with the tungsten-based plasma facing materials, namely plasma wall interaction. Activated tungsten dust would be an emerging environmental pollutant with radiation toxicity containing various radionuclides in addition to the chemical toxicity of tungsten itself. Nonetheless, the historical underestimation of its environmental availability has led to limited research on tungsten compared to other environmental contaminants. This paper presents the first systematic review on the safety issue of emerging activated tungsten dust, encompassing source terms, environmental behaviors, and health effects. The key contents are as follows: 1) to detail the source terms of activated tungsten dust from aspects of tungsten basic properties, generation mechanism, physical morphology and chemical component, radioactivity, as well as potential release pathways, 2) to illustrate the environmental behaviors from aspects of atmospheric dispersion and deposition, transformation and migration in soil, as well as plant absorption and distribution, 3) to identify the toxicity and health effects from aspects of toxicity to plants, distribution in human body, as well as health effects by radiation and chemical toxicity, 4) based on the research progress, research and development issues needed are also pointed out to better knowledge of safety issue of activated tungsten dust, which would be beneficial to the area of fusion energy and ecological impact caused by the routine tungsten related industrial and military applications.

CRKL but not CRKII contributes to hemin-induced erythroid differentiation of CML.

Destruction of erythropoiesis process leads to various diseases, including thrombocytopenia, anaemia, and leukaemia. miR-429-CT10 regulation of kinase-like (CRKL) axis involved in development, progression and metastasis of cancers. However, the exact role of miR-429-CRKL axis in leukaemic cell differentiation are still unknown. The current work aimed to uncover the effect of miR-429-CRKL axis on erythropoiesis. In the present study, CRKL upregulation was negatively correlated with miR-429 downregulation in both chronic myeloid leukaemia (CML) patient and CR patient samples. Moreover, CRKL expression level was significantly decreased while miR-429 expression level was increased during the erythroid differentiation of K562 cells following hemin treatment. Functional investigations revealed that overexpression and knockdown of CRKL was remarkably effective in suppressing and promoting hemin-induced erythroid differentiation of K562 cells, whereas, miR-429 exhibited opposite effects to CRKL. Mechanistically, miR-429 regulates erythroid differentiation of K562 cells by downregulating CRKL via selectively targeting CRKL-3'-untranslated region (UTR) through Raf/MEK/ERK pathway. Conversely, CRKII had no effect on erythroid differentiation of K562 cells. Taken together, our data demonstrated that CRKL (but not CRKII) and miR-429 contribute to development, progression and erythropoiesis of CML, miR-429-CRKL axis regulates erythropoiesis of K562 cells via Raf/MEK/ERK pathway, providing novel insights into effective diagnosis and therapy for CML patients.

SMURF2 predisposes cancer cell toward ferroptosis in GPX4-independent manners by promoting GSTP1 degradation.

Ferroptosis is a non-apoptotic form of regulated cell death. Glutathione (GSH) peroxidase 4 (GPX4) and GSH-independent ferroptosis suppressor protein 1 (FSP1) have been identified as major defenses. Here, we uncover a protective mechanism mediated by GSH S-transferase P1 (GSTP1) by monitoring proteinomic dynamics during ferroptosis. Dramatic downregulation of GSTP1 is caused by SMURF2-mediated GSTP1 ubiquitination and degradation at early stages of ferroptosis. Intriguingly, GSTP1 acts in GPX4- and FSP1-independent manners by catalyzing GSH conjugation of 4-hydroxynonenal and detoxifying lipid hydroperoxides via selenium-independent GSH peroxidase activity. Genetic modulation of the SMURF2/GSTP1 axis or the pharmacological inhibition of GSTP1's catalytic activity sensitized tumor responses to Food and Drug Administration (FDA)-approved ferroptosis-inducing drugs both in vitro and in vivo. GSTP1 expression also confers resistance to immune checkpoint inhibitors by blunting ferroptosis. Collectively, these findings demonstrate a GPX4/FSP1-independent cellular defense mechanism against ferroptosis and suggest that targeting SMURF2/GSTP1 to sensitize cancer cells to ferroptosis has potential as an anticancer therapy.

Long noncoding RNA HITT coordinates with RGS2 to inhibit PD-L1 translation in T cell immunity.

Programmed cell death ligand 1 (PD-L1) is an immune checkpoint protein frequently expressed in human cancers that contributes to immune evasion through its binding to PD-1 on activated T cells. Unveiling the mechanisms underlying PD-L1 expression is essential for understanding the impact of the immunosuppressive microenvironment and is also crucial for the purpose of reboosting antitumor immunity. However, how PD-L1 is regulated, particularly at translational levels, remains largely unknown. Here, we discovered that a long noncoding RNA (lncRNA), HIF-1α inhibitor at translation level (HITT), was transactivated by E2F transcription factor 1 (E2F1) under IFN-γ stimulation. It coordinated with regulator of G protein signaling 2 (RGS2) in binding to the 5' UTR of PD-L1, resulting in reduced PD-L1 translation. HITT expression enhanced T cell-mediated cytotoxicity both in vitro and in vivo in a PD-L1-dependent manner. The clinical correlation between HITT/PD-L1 and RGS2/PD-L1 expression was also detected in breast cancer tissues. Together, these findings demonstrate the role of HITT in antitumor T cell immunity, highlighting activation of HITT as a potential therapeutic strategy for enhancing cancer immunotherapy.

Feasibility Study to Byproduce Medical Radioisotopes in a Fusion Reactor.

Currently, international nuclear fission reactors producing medical isotopes face the problem of shutdown and maintenance, decommissioning, or dismantling, while the production capacity of domestic research reactors for medical radioisotopes is inadequate, and the supply capacity for medical radioisotopes faces major challenges in the future. Fusion reactors are characterized by high neutron energy, high flux density, and the absence of highly radioactive fission fragments. Additionally, compared to fission reactors, the reactivity of the fusion reactor core is not significantly affected by the target material. By building a preliminary model of the China Fusion Engineering Test Reactor (CFETR), a Monte Carlo simulation was performed for particle transport between different target materials at a fusion power of 2 GW. The yields (specific activity) of six medical radioisotopes (14C, 89Sr, 32P, 64Cu, 67Cu, and 99Mo) with various irradiation positions, different target materials, and different irradiation times were studied, and compared with those of other high-flux engineering test reactors (HFETR) and the China Experimental Fast Reactor (CEFR). The results show that this approach not only provides competitive medical isotope yield, but also contributes to the performance of the fusion reactor itself, e.g., tritium self-sustainability and shielding performance.

Calcium homeostasis and cancer: insights from endoplasmic reticulum-centered organelle communications.

Calcium ion (Ca2+) is a ubiquitous and versatile signaling molecule controlling a wide variety of cellular processes, such as proliferation, cell death, migration, and immune response, all fundamental processes essential for the establishment of cancer. In recent decades, the loss of Ca2+ homeostasis has been considered an important driving force in the initiation and progression of malignant diseases. The primary intracellular Ca2+ store, the endoplasmic reticulum (ER), plays an essential role in maintaining Ca2+ homeostasis by coordinating with other organelles and the plasma membrane. Here, we discuss the dysregulation of ER-centered Ca2+ homeostasis in cancer, summarize Ca2+-based anticancer therapeutics, and highlight the significance of furthering our understanding of Ca2+ homeostasis regulation in cancer.

iASPP suppression mediates terminal UPR and improves BRAF-inhibitor sensitivity of colon cancers.

Unfolded protein response (UPR) signaling is activated under endoplasmic reticulum (ER) stress, an emerging cancer hallmark, leading to either adaptive survival or cell death, while the mechanisms underlying adaptation-death switch remain poorly understood. Here, we examined whether oncogene iASPP regulates the switch and how the mechanisms can be used in colon cancer treatment. iASPP is downregulated when cells undergo transition from adaptation to death during therapy-induced ER stress. Blocking iASPP's downregulation attenuates stress-induced cell death. Mechanistically, Hu-antigen R (HuR)-mediated stabilization of iASPP mRNA and subsequent iASPP protein production is significantly impaired with prolonged ER stress, which facilitates the degradation of GRP78, a key regulator of the UPR, in the cytosol. Because iASPP competes with GRP78 in binding the ER-resident E3 ligase RNF185, and tips the balance in favor of cell death. Positive correlation between the levels of HuR, iASPP, and GRP78 are detectable in colon cancer tissues in vivo. Genetic inhibition of iASPP/GRP78 or chemical inhibition of HuR not only inhibits tumor growth, but also sensitizes colon cancer cells' responses to BRAF inhibitor-induced ER stress and cell death. This study provides mechanistic insights into the switch between adaptation and death during ER stress, and also identifies a potential strategy to improve BRAF-inhibitor efficiency in colon cancers.

iASPP suppresses Gp78-mediated TMCO1 degradation to maintain Ca2+ homeostasis and control tumor growth and drug resistance.

Ca2+ release from the endoplasmic reticulum (ER) is an essential event in the modulation of Ca2+ homeostasis, which is coordinated by multiple biological processes, ranging from cell proliferation to apoptosis. Deregulated Ca2+ homeostasis is linked with various cancer hallmarks; thus, uncovering the mechanisms underlying Ca2+ homeostasis dynamics may lead to new anticancer treatment strategies. Here, we demonstrate that a reported Ca2+-channel protein TMCO1 (transmembrane and coiled-coil domains 1) is overexpressed in colon cancer tissues at protein levels but not at messenger RNA levels in colon cancer. Further study revealed that TMCO1 is a substrate of ER-associated degradation E3 ligase Gp78. Intriguingly, Gp78-mediated TMCO1 degradation at K186 is under the control of the iASPP (inhibitor of apoptosis-stimulating protein of p53) oncogene. Mechanistically, iASPP robustly reduces ER Ca2+ stores, mainly by competitively binding with Gp78 and interfering with Gp78-mediated TMCO1 degradation. A positive correlation between iASPP and TMCO1 proteins is further validated in human colon tissues. Inhibition of iASPP-TMCO1 axis promotes cytosolic Ca2+ overload-induced apoptotic cell death, reducing tumor growth both in vitro and in vivo. Thus, iASPP-TMCO1 represents a promising anticancer treatment target by modulating Ca2+ homeostasis.

Blocking iASPP/Nrf2/M-CSF axis improves anti-cancer effect of chemotherapy-induced senescence by attenuating M2 polarization.

The complex interaction between cancer cells and the immune microenvironment is a central regulator of tumor growth and the treatment response. Chemotherapy-induced senescence is accompanied by the senescence-associated secretion phenotype (SASP). However, the mechanisms underlying the regulation of the SASP remain the most poorly understood element of senescence. Here, we show that nuclear erythroid factor 2-like factor 2 (Nrf2), a master antioxidative transcription factor, accumulates upon doxorubicin-induced senescence. This is due to the increased cytoplasmic Inhibitor of Apoptosis Stimulating Protein of P53, iASPP, which binds with Keap1, interrupting Keap1/Nrf2 interaction and promoting Nrf2 stabilization and activation. Activated Nrf2 transactivates a novel target gene of SASP factor, macrophage colony-stimulating factor (M-CSF), which subsequently acts on macrophages and induces polarization from M1 to M2 via a paracrine mechanism. Genetic inhibition of iASPP-Nrf2 suppresses the growth of apoptosis-resistant xenografts, with further analysis revealing that M-CSF/M-CSFR-regulated macrophage polarization is critical for the functional outcomes delineated above. Overall, our data uncover a novel function of iASPP-Nrf2 in skewing the immune microenvironment under treatment-induced senescence. Targeting the iASPP-Nrf2 axis could be a powerful strategy for the implementation of new chemotherapy-based therapeutic opportunities.

iASPP is essential for HIF-1α stabilization to promote angiogenesis and glycolysis via attenuating VHL-mediated protein degradation.

Hypoxia-inducible factor-1α (HIF-1α) plays central roles in the hypoxia response. It is highly expressed in multiple cancers, but not always correlated with hypoxia. Mutation of the von Hippel-Lindau (VHL) gene, which encodes an E3 ligase, contributes to the constructive activation of HIF-1α in specific tumor types, as exemplified by renal cell carcinoma; but how VHL wild-type tumors acquire this ability is not completely understood. Here, we found that the oncogene iASPP (inhibitor of apoptosis-simulating protein of p53) plays essential roles in such a context. Genetic inhibition of iASPP reduced tumor growth, accompanied by impaired angiogenesis, increased areas of tumor necrosis, and reduced glycolysis that was HIF-1α-dependent. These abilities of iASPP were validated by in vitro assays. Mechanistically, iASPP directly binds VHL at its ß domain, a region also involved in HIF-1α binding, therefore blocking VHL's binding and the subsequent degradation of HIF-1α protein under normoxia. iASPP levels correlate with HIF-1α protein and vascular endothelial growth factor (VEGF) and the glucose transporter protein type 1(GLUT1), representative HIF-1α target genes, in human colon cancer tissues. Furthermore, inhibition of iASPP expression synergizes with low toxic dose of the HIF-1α inhibitor YC-1 to inhibit HIF-1α expression and tumor growth. Our findings suggest that iASPP contributes to HIF-1α activation in cancers, and that iASPP-mediated HIF-1α stabilization has potential as a therapeutic approach against cancer.

lncRNA HITT inhibits metastasis by attenuating Rab5-mediated endocytosis in lung adenocarcinoma.

Endocytosis of cell surface receptors is essential for cell migration and cancer metastasis. Rab5, a small GTPase of the Rab family, is a key regulator of endosome dynamics and thus cell migration. However, how its activity is regulated still remains to be addressed. Here, we identified a Rab5 inhibitor, a long non-coding RNA, namely HITT (HIF-1α inhibitor at translation level). Our data show that HITT expression is inversely associated with advanced stages and poor prognosis of lung adenocarcinoma patients with area under receiver operating characteristics (ROC) curve (AUC) 0.6473. Further study reveals that both endogenous and exogenous HITT inhibits single-cell migration by repressing ß1 integrin endocytosis in lung adenocarcinoma. Mechanistically, HITT is physically associated with Rab5 at switch I via 1248-1347 nt and suppresses ß1 integrin endocytosis and subsequent cancer metastasis by interfering with guanine nucleotide exchange factors (GEFs) for Rab5 binding. Collectively, these findings suggest that HITT directly participates in the regulation of Rab5 activity, leading to a decreased integrin internalization and cancer metastasis, which provides important insights into a mechanistic understanding of endocytosis and cancer metastasis.

Nuclear iASPP determines cell fate by selectively inhibiting either p53 or NF-κB.

p53 and NF-κBp65 are essential transcription factors (TFs) in the cellular response to stress. Two signaling systems can often be entwined together and generally produce opposing biological outcomes in a cell context-dependent manner. Inhibitor of apoptosis-stimulating protein of p53 (iASPP) has the potential to inhibit both p53 and NF-κBp65, yet how such activities of iASPP are integrated with cancer remains unknown. Here, we utilized different cell models with diverse p53/NF-κBp65 activities. An iASPP(295-828) mutant, which is exclusively located in the nucleus and has been shown to be essential for its inhibitory effects on p53/NF-κBp65, was used to investigate the functional interaction between iASPP and the two TFs. The results showed that iASPP inhibits apoptosis under conditions when p53 is activated, while it can also elicit a proapoptotic effect when NF-κBp65 alone is activated. Furthermore, we demonstrated that iASPP inhibited the transcriptional activity of p53/NF-κBp65, but with a preference toward p53, thereby producing an antiapoptotic outcome when both TFs were simultaneously activated. This may be due to stronger binding between p53 and iASPP than NF-κBp65 and iASPP. Overall, these findings provide important insights into how the activities of p53 and NF-κBp65 are modulated by iASPP. Despite being a well-known oncogene, iASPP may have a proapoptotic role, which will guide the development of iASPP-targeted therapies to reach optimal outcomes in the future.

Study on volume change and scanning electron microscopy observation of silica-filled solution polymerized styrene-butadiene rubber/cis-1,4-polybutadiene rubber blends upon stretching.

Solution polymerized styrene-butadiene rubber/cis-1,4-polybutadiene rubber (SBR/BR) blends filled with silica is widely used system in tread compounds for passenger tires. The application of silane coupling agents greatly improves the interaction between polymer and filler through chemical bonds. By testing a series of SBR/BR blends filled with different specific surface area and content of silica, we measured the volume change data of the compounds upon stretching and plotted the corresponding ΔV/V-ε curves. In order to normalize for stress differences, ΔV/(Vσ)-ε curves were also plotted using stress-strain data. Scanning electron microscopy (SEM) was used to observe the microstructures in the vulcanizate in situ when stretched. The dispersion, agglomeration, and vacuole formation process can be visualized clearly in the SEM images.

Photothermal conversion-coordinated Fenton-like and photocatalytic reactions of Cu2-xSe-Au Janus nanoparticles for tri-combination antitumor therapy.

In vivo chemical reactions activated by the tumor microenvironment (TME) are particularly promising for antitumor treatments. Herein, employing Cu2-xSe-Au Janus nanoparticles (NPs), photothermal conversion-coordinated Fenton-like and photocatalytic reactions are demonstrated in vitro/vivo. The amorphous form of Cu2-xSe and the catalytic effect of Au benefit the OH generation, and the photo-induced electron‒hole separation of the Janus NPs produces additional OH. The plasmonic electrons of Au facilitate the conversion from Cu2+ to Cu+. Both Cu2-xSe and Au contributes to the efficient photothermal conversion, further promoting the reactions. As a result, the H2O2 utilization rate is largely increased, and remarkable generation of reactive oxygen species is achieved by cell endogenous H2O2in vitro/vivo. A competent tumor inhibition effect is afforded, with high-contrast multimodal imaging. This work opens up the route synergistically integrating photothermal therapy with chemodynamic therapy and photocatalytic therapy into tri-combination antitumor therapy, simply by heterojunction of semiconductor and noble metal.

A previously identified apoptosis inhibitor iASPP confers resistance to chemotherapeutic drugs by suppressing senescence in cancer cells.

Cellular senescence is terminal cell cycle arrest that represents a prominent response to numerous anticancer therapies. The oncogene inhibitor of the apoptosis-stimulating protein of p53 (iASPP) plays essential roles in regulating cellular drug response by inhibiting apoptosis. However, whether or not it regulates chemotherapy-induced senescence (TIS) in cancer cells remains unclear. Here, using two commonly used cancer cell lines, HCT 116 and MCF-7, along with the xenograft mouse model, we found that iASPP inhibits senescence and also influences the senescence-associated secretory phenotype (SASP), which confers anticancer drug resistance independently of apoptosis. Mechanistically, iASPP is transcriptionally elevated by the p65 subunit of NF-κB in senescent cells and then translocates to the nucleus, where it binds p53 and NF-κBp65. This binding inhibits their transcriptional activities toward p21 and the key SASP factors interleukin (IL)-6/IL-8, respectively, and subsequently prevents senescence. Of note, we observed that iASPP knockdown sensitizes apoptosis-resistant cancers to doxorubicin treatment by promoting senescence both in vitro and in vivo We conclude that iASPP integrates the NF-κBp65- and p53-signaling pathways and thereby regulates cell fate in response to TIS, leading to chemotherapy resistance. These findings suggest that iASPP inhibition might be a strategy that could help restore senescence in cancer cells and improve outcomes of chemotherapy-based therapies.

miR-4521-FAM129A axial regulation on ccRCC progression through TIMP-1/MMP2/MMP9 and MDM2/p53/Bcl2/Bax pathways.

Clear cell renal cell carcinoma (ccRCC) is the most aggressive RCC subtype with high metastasis, chemotherapy and radiotherapy resistance, and poor prognosis. This study attempted to establish the deregulations of miR-4521 and FAM129A together with their correlation to and mechanism of regulation of ccRCC development and progression. FAM129A acted as tumor promotor and miR-4521 acted as a suppressor in ccRCC. As measured in surgical tumorous tissues from ccRCC patients, FAM129A overexpression and miR-4521 deficiency together contributed to ccRCC progression by promoting advances in patients' TNM stage and Fuhrman grade. Both the FAM129A knockdown and miR-4521 overexpression could reduce the in vitro migration and invasion abilities of renal cancer cells 786-O and ACHN, through the TIMP-1/MMP2/MMP9 pathway and could decrease their proliferation by promoting their apoptosis through the MDM2/p53/Bcl2/Bax pathway. By directly targeting the 3'-UTR domain of FAM129A, miR-4521 was negatively correlated with FAM129A/FAM129A levels in ccRCC progression and renal cancer cell malignancies. This work establishes the miR-4521-FAM129A axial regulation mechanism in ccRCC. Micro-4521 deficiency leads to FAM129A/FAM129A upregulation, which synergistically enhances the migration and invasion of renal cancer cells due to the induced decrease of TIMP-1 and increases of MMP2 and MMP9, and increases their growth through escaping apoptosis by suppressing p53 by way of upregulation of induced MDM2. The current work provides new clues to assist fundamental research into the diagnosis and treatment of ccRCC.

Selective synthesis of single-crystalline rhombic dodecahedral, octahedral, and cubic gold nanocrystals.

This paper reports a versatile seed-mediated growth method for selectively synthesizing single-crystalline rhombic dodecahedral, octahedral, and cubic gold nanocrystals. In the seed-mediated growth method, cetylpyridinium chloride (CPC) and CPC-capped single-crystalline gold nanocrystals 41.3 nm in size are used as the surfactant and seeds, respectively. The CPC-capped gold seeds can avoid twinning during the growth process, which enables us to study the correlations between the growth conditions and the shapes of the gold nanocrystals. Surface-energy and kinetic considerations are taken into account to understand the formation mechanisms of the single-crystalline gold nanocrystals with varying shapes. CPC surfactants are found to alter the surface energies of gold facets in the order {100} > {110} > {111} under the growth conditions in this study, whereas the growth kinetics leads to the formation of thermodynamically less favored shapes that are not bounded by the most stable facets. The competition between AuCl(4)(-) reduction and the CPC capping process on the {111} and {110} facets of gold nanocrystals plays an important role in the formation of the rhombic dodecahedral (RD) and octahedral gold nanocrystals. Octahedral nanocrystals are formed when the capping of CPC on {111} facets dominates, while RD nanocrystals are formed when the reduction of AuCl(4)(-) on {111} facets dominates. Cubic gold nanocrystals are formed by the introduction of bromide ions in the presence of CPC. The cooperative work of cetylpyridinium and bromide ions can stabilize the gold {100} facet under the growth condition in this study, thereby leading to the formation of cubic gold nanocrystals.

Polarization driven covalently-bonded octahedral-twinning and backbone-peripheral-helical nanoarchitectures.

We report the novel superstructural chiral polar-surface induced backbone-peripheral-helical (BPH) hierarchical architecture of zincblende SiC made possible by precise helical epitaxy. We show by direct image that this architecture has the mother-daughter relationship. The center of the BPH consists of periodic octahedral modular units with chiral sidewalls. By forming Si-C covalent bonds at the sidewalls, a daughter SiC wire spontaneously vine-grows in a peripherally helical way on the mother wire. All of the information of the mother wire, including twinning, polarity and even stacking fault, are completely copied and inherited by the daughter wire one-by-one at the atomic level. Our findings thus provide a simple growth method and the necessary atomistic mechanism for novel polar surface driven superstructural twinning and subsequent BPH growth, which should be universal for zincblende semiconductors and even could be true for other noncentral-symmetric compounds.