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High-dose cyclophosphamide (HD-Cy) (3 g/m2) plus granulocyte colony-stimulating factor (G-CSF) is a very effective regimen for peripheral blood stem cell (PBSC) mobilization. Unfortunately, it is associated with an increased risk of neutropenic fever (NF). We analyzed the effect of NF on PBSC apheresis results and the efficacy of prophylactic antibiotics for the prevention of NF associated with HD-Cy plus G-CSF for PBSC mobilization in patients with newly diagnosed multiple myeloma (MM). First, patients were divided into NF (+) and NF (−) groups according to whether they suffered from NF during mobilization. Second, we divided patients into an antibiotic prophylaxis group and a nonantibiotic prophylaxis group according to whether antibiotic prophylaxis was used during the mobilization period. Our study showed that NF(+) patients (n = 44) had lower CD34 + cell dose collection (median 2.60 versus 5.34 × 106/kg, P < 0.001) and slower neutrophil engraftment and platelet engraftment (median 11 versus 10 days, P = 0.002, and median 13 versus 11 days, P = 0.043, respectively) than NF(−) patients (n = 234). Of note, the nonantibiotic prophylaxis group patients (n = 30) had a 26.7% incidence of NF. In the patients receiving antibiotic prophylaxis (n = 227), the incidence was reduced to 9.3% (P = 0.01). The antibiotic prophylaxis patients had higher CD34 + cell collection (median 5.41 versus 2.27 × 106/kg, P < 0.001) and lower hospitalization cost of mobilization ($ median 3108.02 versus 3702.39, p = 0.012). Thus, our results demonstrate that NF is associated with lower CD34 + cell collection and that antibiotic prophylaxis can reduce the incidence of NF and improve stem cell mobilization and collection outcomes, which reduces the hospitalization cost of mobilization. [ABSTRACT FROM AUTHOR]

Aims: Lymphoepithelioma‐like carcinomas (LELCs) are uncommon epithelial cancers characteristically showing two distinct components consisting of malignant epithelial cells and prominent dense lymphoid infiltrate. Hepatic LELCs consist of two types, the lymphoepithelioma‐like hepatocellular carcinoma and lymphoepithelioma‐like cholangiocarcinoma (LEL‐CCA), with the latter being strongly associated with Epstein–Barr virus (EBV). Methods and results: We present a series of three cases of intrahepatic biliary EBV‐associated LEL tumours in which the biliary epithelial component showed a distinctly benign appearance, instead of the usual malignant epithelial features of a typical CCA or EBV‐associated LEL‐CCA. In the lesions, the biliary epithelium showed interconnecting glands or cords of cells. All had a very low proliferation (Ki‐67) index. Immunohistochemistry for IDH1 and TP53 performed on two cases was negative and molecular tests for EGFR and KRAS gene mutations performed on one were negative. Prognosis was very good in all three cases, with patients alive with no evidence of disease 24–62 months after surgery. Intriguingly, all three cases had co‐infection of HBV and EBV. These cases are also discussed in the context of the 63 cases of LEL‐CCA available in the literature, with a focus on epidemiology, clinicopathological features and potential research interests. Conclusions: Based on the distinct clinicopathological features and unique survival benefits, we believe these tumours represent the benign end of the spectrum of EBV‐associated lymphoepithelial biliary carcinomas. Whether these tumours require a revision of the current nomenclature to 'lymphoepithelioma‐like neoplasm of the biliary tract with probable low malignant potential' will require more detailed analysis with larger case‐series. [ABSTRACT FROM AUTHOR]

Superoxide anion (O 2 •−), the first generated reactive oxygen species (ROS), is a critical player in cellular signaling network and redox homeostasis. Imaging of O 2 •−, particularly in vivo , is of concern for further understanding its roles in pathophysiological and pharmacological events. Herein, we designed a novel probe, (E)-4-(5-(2-(benzo[ d ]thiazol-2-yl)-2-cyanovinyl)furan-2-yl)phenyl trifluoromethane-sulfonate (BFTF), by modifying hydroxyphenyl benzothiazole (a widely used dye scaffold) which includes insertion of both an acrylonitrile unit and a furan ring to extend the total π-conjugation system and to enhance push-pull intramolecular charge transfer process, and utilization of trifluoromethanesulfonate as the response unit. Toward O 2 •−, the probe features near-infrared fluorescent emission (685 nm), large Stokes shift (135 nm), and deep tissue penetration (300 μm). With its help, we successfully mapped preferential generation of O 2 •− in HepG2 cells over L02 cells, as well as in A549 over BEAS-2B cells by β-lapachone (an anticancer agent that generates O 2 •−), and more importantly, visualized overproduction of O 2 •− in living mice with liver injury induced by acetaminophen (a well-known analgesic and antipyretic drug). [Display omitted] • Designing BFTF as a near-infrared O 2 •− probe by modifying benzothiazole. • Identifying that β-lapachone is a prooxidative anticancer agent via O 2 •− generation. • Applying for intravital imaging of O 2 •− overproduction induced by acetaminophen. [ABSTRACT FROM AUTHOR]

This case report discusses a female patient with axial spondyloarthritis (AS) who developed inflammatory bowel disease (IBD) after being treated with secukinumab (SEC), an interleukin-17 inhibitor. The patient had a family history of AS and psoriasis, and her symptoms worsened after starting SEC treatment. She experienced upper abdominal pain, nausea, vomiting, and gastrointestinal bleeding. The report highlights the association between SEC and the exacerbation of gastrointestinal symptoms leading to IBD. It also mentions the low incidence rate of IBD in patients treated with SEC and the lack of reports on neurological damage associated with SEC use. [Extracted from the article]

Simultaneous sensing of cellular microenvironment parameters and redox signaling molecules by a single fluorescent probe allows an efficient access to numerous applications ranging from convenient diagnostic assays to investigation on their pathophysiological roles and cross-link. Focusing on a lack of efficient molecule tools for simultaneous intravital imaging of mitochondrial viscosity and superoxide radical anion (O 2 •-), we bridged diethylaminobenzene with diphenylphosphinate-modified pyridinium moiety by an olefinic bond to construct a styrylpyridinium-based two-photon fluorescent probe V-OS. V-OS triggered a turn-on response either at 625 nm to viscosity which blocks intramolecular rotation, or at 530 nm to O 2 •- via nucleophilic attack of O 2 •- followed by 1,6-elimination. With the aid of the two-photon probe, we not only identified the cross-talk between viscosity and O 2 •- but successfully mapped the burst of O 2 •- and the increased viscosity during either cellular ferroptosis process or cerebral ischemia reperfusion injury of living mice. [Display omitted] • Simultaneous imaging of mitochondrial viscosity and O 2 •- by a single fluorescent probe V-OS. • Turn-on response of V-OS to viscosity and O 2 •- at well-separated red and green channels. • Identifying the cross-talk between viscosity and O 2 •-. • Visualizing the generation of O 2 •- and the increased viscosity during cellular ferroptosis process. • Mapping the burst of O 2 •- and the increased viscosity during cerebral ischemia reperfusion injury in living mice. [ABSTRACT FROM AUTHOR]

In this paper, excellent performance W-Cu-Ni-Fe alloys with the addition of Ni and Fe (total content: 5 wt%) were successfully prepared by low temperature liquid-phase sintering, using the raw material of ultrafine W-Cu-Ni-Fe composite powder. Ultrafine W-Cu-Ni-Fe composite powder with high sintering activity and uniform composition distribution was prepared by a two-stage reduction method consisting of carbothermal reaction and hydrogen deep deoxidation. Additions of Ni and Fe not only improved the wettability between W and Cu two phases, but also improved the bonding strength of two-phase interface. All sintered samples had higher relatively densities to ensure that the samples have great comprehensive properties. When Ni and Fe were co-added in appropriate proportions, the highest tensile strength and elongation of W-Cu-Ni-Fe alloy samples were 497 MPa and 9.12 % for the composition: W-3.5 wt%Ni-1.5 wt%Fe-25 wt%Cu, respectively. Meanwhile, with increasing Ni content from 0 wt% to 5 wt%, the compressive strength and failure strain of alloy samples increased from 1160 MPa to 2376 MPa and from 53 % to 98 %, respectively. In addition, with the enhancement of the solid solution strengthening effects of Ni and Fe on Cu matrix, the bending strength and microhardness of the alloy samples increased to 1174 MPa and 361 HV for composition: W-3.5 wt%Ni-1.5 wt%Fe-25 wt%Cu, respectively. Although the additions of Ni and Fe made the Cu matrix network structure have a uniform distribution, it led to a decrease in the electron transfer ability of the alloy, and thus, there was a decrease in electrical conductivity. [Display omitted] • W-γ-(Cu, Ni, Fe) alloys are successfully prepared. • Addition of Ni and Fe improves the wettability of the W-γ-(Cu, Ni, Fe) interface. • W-γ-(Cu, Ni, Fe) alloy containing 3.5 wt% Ni, 1.5 wt% Fe has excellent comprehensive properties [ABSTRACT FROM AUTHOR]

Boronate-based fluorescent probes are widely used for the imaging of hydrogen peroxide (H 2 O 2). However, their selectivity might be subjected to the interference of other reactive oxygen species, especially peroxynitrite (ONOO-), due to the reaction of boronates with ONOO- being several orders of magnitude faster than with H 2 O 2. This work highlights a doubly activated electrophilicity-increasing strategy to develop a boronate-based fluorescent probe THMP for selective imaging of H 2 O 2 over ONOO-, where a boronate-modified pyridiniumylacrylonitrile is grafted on the 2-(2′-hydroxy-3′-methoxyphenyl) benzothiazole scaffold. Specifically, the boronate oxidation of THMP by H 2 O 2 leads to the release of the free fluorophore THMP-N, triggering a ratiometric fluorescence response from red to green. The presence of a doubly activated electrophilic site on the carbon-carbon double bond of THMP, by both the strong electron-withdrawing cyano group and the pyridinium moiety, allows selective oxidative cleavage of the double bond by ONOO- to an aldehyde HMBT-CHO, thereby excluding the interference of ONOO- in monitoring H 2 O 2. With the aid of the probe, we successfully visualized increased levels of H 2 O 2 during ferroptosis of HepG2 cells, and burst of H 2 O 2 in brains of live mice during cerebral ischemia reperfusion injury. [Display omitted] • Highlighting a doubly activated electrophilicity-increasing strategy. • Developing a boronate-based fluorescent probe THMP based on the strategy. • Selective imaging of H 2 O 2 over ONOO- by THMP. • Detailed mechanistic investigation. • Visualizing H 2 O 2 in brains of live mice during cerebral ischemia reperfusion. [ABSTRACT FROM AUTHOR]

Although selective COX-2 inhibitors have cancer-preventive effects and induce apoptosis, the mechanisms underlying these effects are not fully understood. This study investigated the effects of nimesulide, a selective COX-2 inhibitor, on apoptosis and on the JAK/STAT signaling pathway in Eca-109 human esophageal squamous carcinoma cells. The effects and mechanisms of nimesulide on Eca-109 cell growth were studied in culture and in nude mice with Eca-109 xenografts. Cells were cultured with or without nimesulide and/or the JAK2 inhibitor AG490. Cell proliferation was evaluated using the MTT assay, and apoptosis was investigated. COX-2 mRNA expression was measured using reverse transcription polymerase chain reaction, and protein expression was detected by Western blot analysis, immunohistochemistry, and flow cytometry. Nimesulide significantly inhibited Eca-109 cell viability in vitro in a dose- and time-dependent manner ( P < 0.05). Nimesulide also induced apoptosis, which was accompanied by a significant decrease in the expression of COX-2 and survivin and an increase in caspase-3 expression. Nimesulide downregulated the phosphorylation levels of JAK2 and STAT3, and JAK2 inhibition by AG490 significantly augmented both nimesulide-induced apoptosis and the downregulation of COX-2 and survivin ( P < 0.05). In vivo , nimesulide inhibited the growth of Eca-109 tumors and the expression of p-JAK2 and p-STAT3. Thus, nimesulide downregulates COX-2 and survivin expression and upregulates caspase-3 expression in Eca-109 cells, by inactivating the JAK2/STAT3 pathway. These effects may mediate nimesulide-induced apoptosis and growth inhibition in Eca-109 cells in vitro and in vivo . [ABSTRACT FROM AUTHOR]

93W-4.9Ni-2.1Fe-(0.75ZrB 2) alloys (wt%) were subjected to liquid phase sintering and vacuum heat treatment to optimize the microstructure and improve mechanical performance. Microstructural observations demonstrated that W–W continuity, dihedral angle and connectivity after heat-treatment remarkably decreased by 0.75, 10° and 0.7, respectively. Meanwhile, matrix phase volume fraction also increased by nearly 3%, which overcame the negative effects of non-homogeneous microstructure. However, densification and W grain size exhibited marginal changes. Mechanical properties strongly varied with the change of microstructural characteristics. Particularly, as matrix phase volume fraction increased and W–W contiguity decreased dramatically, elongation showed a distinct increasing tendency (from 18.6% to 22.4% in 93W alloys and from 17.5% to 19.5% in 93W-0.75ZrB 2 alloys, respectively). Excellent W-matrix bonding strength improved the tensile property, while microstructure uniformity caused the decrease of hardness value (about 28 HV 1). Furthermore, the relationship between mechanical properties and fracture mode was analyzed. [Display omitted] • Significant changes occurred in the microstructure after vacuum heat treatment. • Improved elongation and UTS of WHAs associated with heat treatment process. • The change of mechanical properties is related to the microstructure evolution. • W cleavage and matrix rupture are dominant fracture modes for heat-treated WHAs. [ABSTRACT FROM AUTHOR]

[Display omitted] • Fine-grained W-Cu alloy with dispersed Al 2 O 3 particles is successfully prepared. • The lower Al 2 O 3 addition content, the smaller W grain size and W-W connectivity. • W-Cu alloy containing 0.5 wt% Al 2 O 3 has excellent comprehensive properties. In this study, high-performance fine-grained W-Cu sintered blocks with the addition of dispersed Al 2 O 3 particles were successfully produced by low temperature liquid-phase sintering, using the raw material of ultrafine W-Cu alloy powder. The ultrafine W-Cu alloy powder was obtained by a two-step reduction process composed of stages of carbothermal reaction and hydrogen deep deoxidation. The fine Al 2 O 3 grains with uniform distribution in W-Cu alloy were introduced by spray method, leading to the decrease of W grain size and W-W connectivity. The relative densities of all sintered blocks were>97%, and a higher degree of densification ensures that the alloy has excellent comprehensive properties. With the increase of Al 2 O 3 content, W grain size and W-W connectivity of sintered W-Cu samples decrease from 664 nm to 472 nm and 0.2 to 0.14, respectively. The W-Cu alloy with the ultimate tensile strength of 415 MPa and the highest elongation of 7.22% was obtained when the addition amount of Al 2 O 3 was 0.5 wt%. At the same time, it also possessed the maximum bending strength of 1028 MPa and microhardness of 312 HV, respectively. In addition, due to the good network structure of Cu and uniform three-phase distribution, the sintered samples had excellent conductivity and compressive strength. [ABSTRACT FROM AUTHOR]

Powder metallurgy approach was used to produce fine-grain tungsten heavy alloys (WHAs), and the effect of Mo addition on the microstructures and mechanical properties of the alloy was discussed. The W-Mo-Ni-Fe ultrafine composite powders were prepared via method consisting of steps of carbothermic pre-reduction and subsequent deep hydrogen reduction. The sintered compacts of these W-Mo-Ni-Fe composite powders reached virtually full densification after sintering at 1500 °C for 2 h. It was discovered that the W grain size of WHAs reduced due to the Mo addition (0, 2.5, 5, 10 wt%). Tensile test results showed that the alloy with 5 wt% Mo exhibited the maximum ultimate tensile strength and elongation, which has a significant relationship with finer W grain size, lower W W contiguity and higher volume fraction of the γ-(Ni, Fe) matrix phase. It was also concluded that the major fracture characteristic of WHAs were transformed from W W decohesion to W-matrix interface separation with increasing the addition amount of Mo. • Fine-grained W-Mo-Ni-Fe alloys were prepared from ultrafine W-Mo-Ni-Fe composite powder. • W grain size decreases with the Mo addition. • Alloy with 5 wt.% Mo exhibited maximum ultimate tensile strength and elongation. [ABSTRACT FROM AUTHOR]

Abstract: Aim: It is of clinical importance to find methods to overcome bortezomib resistance. In the current study, we clarified the relationship between resistance to bortezomib and the differentiation status of myeloma cells, and explored the feasibility of induction of differentiation in overcoming bortezomib resistance in myeloma. Methods: Cell morphology, immunoglobulin light-chain protein secretion levels, and XBP-1 expression were used to evaluate the differentiation status of myeloma cells. Low dose 2-ME2 alone or in combination with ATRA was used to induce differentiation in myeloma cells. Results: The differentiation status of myeloma cells was related to myeloma sensitivity to bortezomib. After successful induction of differentiation, the myeloma cells were more sensitive to bortezomib with decreased growth and an increased rate of apoptosis. Induction of differentiation increased the proteasome workload in myeloma cells by increasing immunoglobulin secretion, while reducing proteasome capacity by decreasing proteasome activity. The imbalance between increased proteasome workload and decreased proteasome capacity is a possible mechanism by which induction of differentiation overcomes myeloma resistance to bortezomib. Conclusion: The current study demonstrated, for the first time, that myeloma differentiation status is associated with myeloma sensitivity to bortezomib and that induction of differentiation can overcome myeloma resistance to bortezomib. [Copyright &y& Elsevier]

A novel ratiometric fluorescent probe derived from 2-(2′-hydroxy-3′-methoxyphenyl) benzothiazole (HMBT) for human carboxylesterase 1 (hCES1) has been synthesized and well characterized. The probe was designed by modulating the excited state intramolecular proton transfer (ESIPT) emission of HMBT via introducing of an octanoyl group. Under physiological conditions, the probe displayed satisfying stability with very low background fluorescence signal at 489 nm, but it could be selectively hydrolyzed by hCES1 to release its metabolite HMBT which brings remarkable changes in fluorescence spectrum. The newly designed probe exhibited excellent selectivity towards hCES1 over other enzymes, while the interference of endogenous chemicals was negligible. The probe can be used for accurately measuring the actual activities of hCES1 in complex biological samples. The potential biological applications of the probe including inhibitor screening, quantification of hCES1 in serum, as well as fluorescence imaging in vivo, have been demonstrated. Image 1 • An ESIPT-based fluorescent probe with large Stokes shift has been developed for detection of human carboxylesterase 1. • The probe can be selectively hydrolyzed by hCES1 which brings remarkable changes in fluorescence spectrum. • The probe can be used for accurately measuring the actual activities of hCES1 in complex biological samples. • The potential biological applications of the probe included inhibitor screening, as well as fluorescence imaging in vivo. [ABSTRACT FROM AUTHOR]