Search

40CrNiMoA steel was nitrided by arc plasma-assisted nitriding (PAN) process at 430 °C, 1 Pa for 3 h with different N2/Ar ratios. Their structures, micrographs, microhardness profiles and tribological properties were investigated by X-ray diffraction (XRD), optical microscope, SEM, Vickers microhardness tester and pin-on-disk tribometer, respectively. All of the nitrided layers were primarily consisted of the γ′-Fe4N and ε-Fe3N. The thickness of compound layers increased with the N2/Ar ratio increasing. The maximum thickness of the compound layer was about 6 μm after nitriding, while the thickness of nitrided layer reached about 230 μm. The surface microhardness and wear resistance of the steel were significantly improved. Its maximum surface microhardness enhanced as 3 times (approx.) as that of the substrate. The wear mechanism changed from adhesive wear to abrasive wear. In addition, the nitrided sample treated at N2/Ar ratio of 75%:25% had the optimum abrasion resistance and lowest wear rate.

Plasma electrolytic oxidation (PEO) coatings were prepared using a pulsed bipolar power supply to investigate the effects of different cathodic currents on the growth mechanism of PEO coatings on 6061 aluminum alloy. The phase composition, microstructure, element distribution and content of the coatings were analyzed by X-ray diffraction (XRD), scanning electron microscope (SEM) and energy dispersive spectroscopy (EDS). It was found that the coating growth rate enhanced obviously and the discrete pores reduced significantly when the cathodic current increased. In particular, when the cathodic current density was 7.5 A/dm2, there was a soft plasma discharge phenomenon, and more α-Al2O3crystals were generated. The distribution of Si elements reveals that the soft plasma discharge is a form of internal discharge and the coating exhibits higher hardness and compactness. It was tested using the friction tester, and the coating showed excellent wear resistance.

Secondary mutations of FLT3 have become the main mechanism of FLT3 inhibitor resistance that presents a significant clinical challenge. Herein, a series of pyrazole-3-amine derivatives were synthesized and optimized to overcome the common secondary resistance mutations of FLT3. The structure–activity relationship and molecular dynamics simulation studies illustrated that the ribose region of FLT3 could be occupied to help address the obstacle of secondary mutations. Among those derivatives, compound 67exhibited potent and selective inhibitory activities against FLT3-ITD-positive acute myeloid leukemia (AML) cells and possessed equivalent potency against transformed BaF3 cells with a variety of secondary mutations. Besides, cellular mechanism assays demonstrated that 67strongly inhibited phosphorylation of FLT3 and its downstream signaling factors, as well as induced cell cycle arrest and apoptosis in MV4-11 cells. In the MV4-11 xenograft models, 67exhibited potent antitumor potency without obvious toxicity. Taken together, these results demonstrated that 67might be a drug candidate for the treatment of FLT3-ITD-positive AML.

Element doping and nano-inclusion embedding are effective approaches to enhance the electrical conductivities and decrease the lattice thermal conductivities of thermoelectric (TE) materials, respectively. However, the intrinsic low electrical thermal conductivities and high electrical properties are severely sacrificed, and the final figure of merit (ZT) is usually restricted. In this study, Ag doping and Pt quantum dot (QD) embedding were synchronously achieved viaembedding Ag/Pt alloy QDs into the higher manganese silicides to avoid the conventional single-element doping strategy. The power factor (at 823 K) was enhanced from 1.57 × 10−3 W m−1 K−2to 1.82 × 10−3 W m−1 K−2(∼16%) due to the ∼18% increase in carrier concentration that was derived from the Ag doping effect. Simultaneously, the lattice thermal conductivity (at 823 K) decreased from 2.65 W m−1 K−1–1.92 W m−1 K−1(∼28%) because of the broadband phonon scattering effect that resulted from the residual Pt QDs inclusions. Synthetically, the optimal ZTvalue increased by ∼52% from 0.42 to 0.64 at 823 K. This study demonstrated that incorporating metastable alloy QDs to obtain element doping and nano-inclusion embedding effects is a novel and feasible means to enhance the ZTvalue of HMS. This method is also possibly applicable to other alloy QD/TE composites.

We consider a risk model perturbed by a Brownian motion, where the individual claim sizes are dependent on the inter-claim times. We study the Gerber–Shiu functions when ruin is due to a claim or the jump-diffusion process. Integro-differential equations and Laplace transforms satisfied by the Gerber–Shiu functions are obtained. Then, it is shown that the expected discounted penalty functions satisfy defective renewal equations. Explicit expressions can be obtained for exponential claim sizes. Finally, a numerical example is provided to measure the impact of the various dependence parameters in the risk model on the ruin probabilities.

Graphical Abstract:

AbstractWe explore the first passage problem for sticky reflecting diffusion processes with double exponential jumps. The joint Laplace transform of the first passage time to an upper level and the corresponding overshoot is studied. In particular, explicit solutions are presented when the diffusion part is driven by a drifted Brownian motion and by an Ornstein–Uhlenbeck process.

BackgroundBirt-Hogg-Dubé Syndrome (BHDS) characterised by skin fibrofolliculomas, kidney tumour and pulmonary cysts/pneumothorax is caused by folliculin (FLCN) germline mutations. The pathology of both neoplasia and focused tissue loss of BHDS strongly features tissue-specific behaviour of the gene. Isolated cysts/pneumothorax is the most frequent atypical presentation of BHDS and often misdiagnosed as primary spontaneous pneumothorax (PSP). Deferential diagnosis of BHDS with isolated pulmonary presentation (PSP-BHD) from PSP is essential in lifelong surveillance for developing renal cell carcinoma.MethodsThe expression profiles of microRNAs (miRNAs) in cystic lesions of PSP-BHD and PSP were determined via microarray. The selected upregulated miRNAs were further confirmed in the plasma of an expanded cohort of PSP-BHD patients by reverse transcription quantitative PCR (RT-qPCR). Their diagnostic accuracy was evaluated. Moreover, the cellular functions and targeted signalling pathways of FLCN-regulated miRNAs were assessed in various cell lines and in the lesion tissue contexts.ResultsCystic lesions of PSP-BHD and PSP showed different miRNAs profiles with a significant upregulation of miR-424–5p and let-7d-5p in PSP-BHD. The combination of the two effectively predicted BHDS patients. In vitro studies revealed a suppressive effect of FLCN on miR-424–5p and let-7d-5p expressions specifically in lung epithelial cells. The ectopic miRNAs triggered epithelial apoptosis and epithelial transition of mesenchymal cells and suppressed the reparative responses in cells and tissues with FLCN deficiency.ConclusionThe upregulation of miR-424–5p and let-7d-5p by FLCN deficiency occurred in epithelial cells and marked the PSP-BHD condition, which contributed to a focused degenerative pathology in the lung of PSP-BHD patients.

AbstractIn this paper we derive several explicit results on one special sticky diffusion process which is constructed as a time-changed version of a diffusion with no sticky points. A theorem concerning the process-related Green operators defined on some nonnegative piecewise continuous functions is provided. Then, based on this theorem, we explore the distributional properties of the sticky diffusion. A financial application is presented where we compute the value of the European vanilla call option written on the underlying with sticky price dynamics.

Tetracycline (TCN) is a typical antibiotic with ecological toxicity, which is easy to cause bacterial drug resistance. Single-atom catalysts have a broad application prospect in the remediation of antibiotic polluted water by activated persulfate (PDS), but its catalytic properties are limited because of its high surface energy and easy aggregation. Therefore, in our manuscript, a novel nitrogen doped magnetic graphene oxide confined Fe-Co dual single-atom catalyst (Fe/Co(1:1)(S)-NMGO) was prepared by one-step molten salt assisted high temperature pyrolysis. XPS and AC-HAADF-STEM analysis indicated single-atom Fe and Co existed. Fe and Co atoms were bound to the material mainly through coordination with pyridinic N and pyrrolic N. While single-atom Fe and Co were simultaneously introduced into the modified materials, the removal rate of TCN reached 93.1%, implying the significant synergistic effect of single-atom Fe and Co on TCN removal. Molten salt assisted high-temperature pyrolysis significantly improved the TCN degradation rate. In addition, this research showed that the existence of magnetite nanoparticles was beneficial to improve the separation performance of the single-atom catalysts as well as the catalytic performance. At the same time, the effects of some key parameters (Fe/Co molar ratio, catalyst dosage, PDS dosage, initial pH, coexisting anions and humic acids) on TCN degradation in Fe/Co(1:1)(S)-NMGO/PDS system were also investigated. The catalytic potential in actual water and regeneration performance of the material were also evaluated. The possible activation mechanism and degradation pathway of TCN were proposed. These findings will provide important reference for the future design and application of single-atom-involved catalysts.

In recent years, there has been an increasing focus on the application of hydrogels in tissue engineering. The integration of 3D bioprinting technology has expanded the potential applications of hydrogels. However, few commercially available hydrogels used for 3D biological printing exhibit both excellent biocompatibility and mechanical properties. Gelatin methacrylate (GelMA) has good biocompatibility and is widely used in 3D bioprinting. However, its low mechanical properties limit its use as a standalone bioink for 3D bioprinting. In this work, we designed a biomaterial ink composed of GelMA and chitin nanocrystal (ChiNC). We explored fundamental printing properties of composite bioinks, including rheological properties, porosity, equilibrium swelling rate, mechanical properties, biocompatibility, effects on the secretion of angiogenic factors and fidelity of 3D bioprinting. The results showed that adding 1% (w/v) ChiNC to 10% (w/v) GelMA improved the mechanical properties and printability of the GelMA hydrogels, promoted cell adhesion, proliferation and vascularization and enabled the printing of complex 3D scaffolds. This strategy of incorporating ChiNC to enhance the performance of GelMA biomaterials could potentially be applied to other biomaterials, thereby expanding the range of materials available for use. Furthermore, in combination with 3D bioprinting technology, this approach could be leveraged to bioprint scaffolds with complex structures, further broadening the potential applications in tissue engineering.

Isoflurane, a commonly used volatile anesthetic, causes widespread neuronal apoptosis in the developing brain of rodents. Signal transducer and activator of transcription-3 (STAT3) signaling is crucial for cell survival during the neural network establishment period. The aim of this study was to determine whether isoflurane would target STAT3 to deliver its neurotoxicity. Mice at postnatal day 7 and primary cortical neurons cultured for 5 days were treated with isoflurane. Our data showed that isoflurane exposure downregulated the STAT3 survival pathway in the brain of mice and in primary neurons, whereas the mRNA levels of STAT3 remained unchanged after isoflurane exposure. We found that inhibiting the activity of calcineurin, which specifically promotes STAT3 degradation, alleviated isoflurane-induced neural apoptosis. Further studies showed that isoflurane increased calcineurin activity and that the inositol 1,4,5-trisphosphate-sensitive Ca2+channel was involved in these isoflurane-induced molecular cascades. These findings suggest that isoflurane-induced neurotoxicity may stem from STAT3 degradation, partially through the activation of calcineurin.

ABSTRACTHuman papillomaviruses (HPVs) are small DNA tumor viruses that are the causative agent of warts and are associated with many anogenital cancers. The viral gene encoding the E6 protein has been found to be involved in HPV oncogenesis. E6 is known to inactivate the cellular tumor suppressor, p53. In addition, E6 has been shown to bind to a variety of other cellular proteins. The focus of this study was to determine what role the interactions of E6 with a subset of cellular proteins which contain a common a-helical domain in their E6 binding region (a-helix partners) play in E6-mediated phenotypes. We generated transgenic mice expressing a mutant of E6, E6I128T, which is defective for binding at least a subset of the a-helix partners, including E6AP, the ubiquitin ligase that mediates E6-dependent degradation of the p53 protein, to determine whether binding of a-helix partners plays a role in E6-mediated activities in vivo. Unlike mice expressing the wild-type E6 (strain K14E6WT), the mice expressing E6I128Tlacked the ability to alter the radiation-induced block to DNA synthesis and promote the formation of benign skin tumors in conjunction with chemical carcinogens. Additionally, they displayed reduced levels of skin hyperplasia, spontaneous skin tumors, and tumor progression activity compared to those of the K14E6WTmice. From these results, we conclude that a domain in E6 that mediates a-helix partner binding is critical for E6-induced phenotypes in transgenic mice.

High-risk human papillomaviruses (HPVs) are etiologically implicated in human cervical cancer. Two viral genes, E6 and E7, are commonly found expressed in these cancer cells. We have previously shown that mice transgenic for the HPV-16 E6 gene or E7 gene, in which the E6 or E7 was expressed in the basal layer of epithelia, developed skin tumors. The spectrum of tumors derived from E6 and E7 mice differed, however; although most tumors derived from the E7-transgenic mice were benign, the majority of the tumors from the E6-transgenic mice were malignant. These findings led us to hypothesize that E6 and E7 play different roles in carcinogenesis. To assess at what stages in carcinogenesis E6 and E7 act, we treated the skin of K14E6- and K14E7-transgenic mice with chemical carcinogens known to contribute to distinct stages in carcinogenesis. Both E6 and E7 were found to synergize with chemical carcinogens in causing tumor formation. E6 was found to act weakly at the promotion stage of carcinogenesis in the formation of benign tumors but strongly at the progression stage which involves the malignant conversion of benign tumors. In contrast, E7 primarily affected the promotion stage of carcinogenesis. These results provide direct evidence that E6 and E7 contribute differently to carcinogenesis; E7 promotes the formation of benign tumors, and E6 acts primarily to accelerate progression of these benign tumors to the malignant stage. Consistent with this model, we found E6 and E7 to cooperate in inducing tumor formation in mice expressing both oncogenes.

Different parts of the skin respond to ionizing radiation with different sensitivities. To examine the mechanisms underlying these different responses, we investigated various cellular parameters in the skin after exposure of mice to 5 Gy of ionizing radiation. Epidermal cells responded to radiation by undergoing growth arrest, whereas the cells in the matrix of hair follicles underwent apoptosis but not growth arrest. These distinct responses correlated with differential increases in p53 and p21 proteins in these two populations of cells; whereas an increase in p53 protein levels was observed in both epidermis and hair follicular matrix, especially in the latter, the induction of p21 was strong in the epidermis but absent in the follicular matrical cells. Studies using p53-null and p21-null mice demonstrated that the radiation-induced apoptosis in the hair follicles was fully dependent on p53, and growth arrest in the epidermis was only partially dependent on p53 but fully dependent on p21. These results indicate that two epithelial cell types respond to radiation by different pathways that are governed in part by the differential p53- and p21-dependent responses of these cells; high-level induction of p53 in the absence of p21 induction led to apoptosis, whereas intermediate induction of both p53 and p21 led to growth arrest.

ABSTRACTHigh-risk human papillomaviruses (HPVs) are the causative agents of certain human cancers. HPV type 16 (HPV16) is the papillomavirus most frequently associated with cervical cancer in women. The E6 and E7 genes of HPV are expressed in cells derived from these cancers and can transform cells in tissue culture. Animal experiments have demonstrated that E6 and E7 together cause tumors. We showed previously that E6 and E7 together or E7 alone could induce skin tumors in mice when these genes were expressed in the basal epithelia of the skin. In this study, we investigated the role that the E6 gene plays in carcinogenesis. We generated K14E6 transgenic mice, in which the HPV16 E6 gene was directed in its expression by the human keratin 14 promoter (hK14) to the basal layer of the epidermis. We found that E6 induced cellular hyperproliferation and epidermal hyperplasia and caused skin tumors in adult mice. Interestingly, the tumors derived from E6 were mostly malignant, as opposed to the tumors from E7 mice, which were mostly benign. This result leads us to hypothesize that E6 may contribute differently than E7 to HPV-associated carcinogenesis; whereas E7 primarily contributes to the early stages of carcinogenesis that lead to the formation of benign tumors, E6 primarily contributes to the late stages of carcinogenesis that lead to malignancy.

Neale: CHRB: Research Funding.

Immune reconstitution following stem cell transplantation (SCT) may be considered as a dynamical system in which future events are predicated on all the preceding past events. In turn, lymphoid reconstitution over time will determine the clinical trajectory an individual patient might take. Lymphoid recovery following myeloablative stem cell transplantation (SCT) displays a logistic (sigmoidal) pattern of exponential growth followed by a plateau. This study aims to understand whether logistic modeling of lymphocyte recovery following SCT can be used to predict outcomes and thus guide therapies to minimize the competing pathologies of graft vs. host disease (GVHD) and relapse. A retrospective analysis of allogeneic SCT performed from 2008 to 2011 was undertaken to compare lymphoid recovery and clinical outcomes in 82 patients with acute myelogenous leukemia, acute lymphocytic leukemia and myelodysplastic syndromes. Using Prismsoftware,a logistic curve was successfully fitted to the absolute lymphocyte count recovery in all patients. Patients were classified according to the magnitude and rate of lymphoid recovery; Type A achieved an absolute lymphocyte count (ALC) of > 1000/mcrL by day 45; Type B an ALC 500

Severe graft versus host disease (GVHD) continues to compromise transplant outcomes following reduced intensity (RI) allogeneic stem cell transplantation (SCT). ATG reduces the risk of GVHD in unrelated donor (URD) stem cell transplant (SCT) recipients. Here we report the results of a randomized phase II clinical trial evaluating two doses of rabbit ATG (Thymoglobulin, Sanofi Aventis) 5.1 (ATG5) and 7.5 mg/kg (ATG7.5) administered along with 450 cGy total body irradiation (TBI). This study followed an earlier trial which examined the optimal schedule of ATG administration in this regimen (Toor et al, BMT 2008). ATG was administered from day -9 to day -7, and fractionated TBI on day -1 and 0. Tacrolimus and mycophenolate mofetil were administered for GVHD prophylaxis.Forty-one patients with advanced hematologic malignancies were randomized and conditioned with ATG-TBI, stratified according to donor type, HLA-matched related (MRD) or unrelated (URD) donor. ATG5 had 10/19 URD recipients compared to 12/22 ATG7.5. Median age of the patients was 57; 9 patients had MM, 15 NHL, 12 CLL/PLL and 6 MDS/AML. Twenty-six were in CR at SCT (11 ATG5, 15 ATG7.5), 13 were in PR/SD (7 and 6 in the two arms) and 2 (1 in each arm) were in untreated relapse. Median number of prior therapies was 4 in each arm; 6 (ATG5) and 9 (ATG7.5) patients had a prior autologous SCT.Myeloid engraftment occurred at a median of 12 days after stem cell infusion in both arms; median neutrophil chimerism at 4, 8, 12 and 24 weeks was 0% recipient in both arms. Persistent mixed T cell chimerism was observed more frequently in the ATG7.5 arm with a trend toward full donor chimerism over time in the ATG5 patients (Figure 1); mean T cell chimerism was 14% in ATG5 and 25% in ATG7.5 at 4 weeks; 8 and 26 (repeated measures ANOVA p=0.058) at 8 weeks; 9 and 31 (RMANOVA p=0.016) at 12 weeks; and 6 and 27 (p=0.029) at 24 weeks respectively. Mean donor derived T cell counts (ddCD3; product of absolute CD3+ cell count and donor T cell chimerism) were 182/microliter, 1080, 872, 876 in ATG5 and 182, 290, 296, 445 in ATG7.5 patients at the corresponding time points, being significantly larger in the ATG5 arm compared to ATG7.5 at 8 (p = 0.008) and 12 weeks (p = 0.052). The changes in ddCD3 between successive months were significantly larger in the ATG5 cohort between 1 and 2 months (p = 0.004). Further, 2 patients in the ATG7.5 arm developed secondary graft loss indicating more robust engraftment in the ATG5 cohort, likely due to superior immune reconstitution.There was no significant difference in the survival between arms (Log-Rank P = 0.8). The 2-year survival rates were 64% (95%CI: 61%, 67%) ATG5 and 54% (95%CI: 50%, 58%) ATG7.5. Day 100 TRM was 0% in both arms; classical onset grade III-IV acute GVHD was not observed in either arm, 2 patients in the ATG7.5 arm developed grade II acute GVHD. Delayed onset acute GVHD occurred in 5 patients in the ATG5 cohort, (3 Grade III-IV) and 4 ATG7.5 (2 Grade III-IV) following early tapering of immunosuppression. Chronic GVHD occurred in 2 patients in ATG5 (1 mild, 1 severe) compared to 7 in ATG7.5 cohort (2 mild, 1 moderate, 4 severe). Overlap syndrome occurred in 2 in ATG5 patients and none in ATG7.5 cohort. GVHD was observed more frequently in patients with higher ddCD3 counts at 8 weeks. Relapse occurred in 26% vs 27%, ATG5 and ATG7.5 (Grey's test P=0.9). Two patients in the ATG5 cohort needed donor lymphocyte infusions (DLI) compared to 8 in ATG7.5 (Grey's test P = 0.07); 6 of these patients received prophylactic DLI for declining donor chimerism (5 in the ATG 7.5 cohort). A composite index (relapse, DLI, non-relapse mortality) was not significantly different between the cohorts (Log Rank P = 0.9). High-dose valacyclovir was used for CMV prophylaxis; CMV reactivation (>1000 copies/microl) developed in 2 ATG5 patients and 3 in ATG7.5 arm; EBV reactivation (>10 copies/microl) developed in 1 and 2 patients respectively in the two cohorts.In summary our clinical trial demonstrates that ATG5 in combination with low dose TBI yields optimal T cell engraftment, with an excellent safety profile and good clinical outcomes, and may serve as a platform for adoptive immunotherapy. Phase III clinical trial comparing this regimen with more established regimens for RI-SCT is being planned.Toor: Sanofi Avnetis: Research Funding.

Severe graft versus host disease (GVHD) continues to compromise transplant outcomes following reduced intensity (RI) allogeneic stem cell transplantation (SCT). ATG reduces the risk of GVHD in unrelated donor (URD) stem cell transplant (SCT) recipients. Here we report the results of a randomized phase II clinical trial evaluating two doses of rabbit ATG (Thymoglobulin, Sanofi Aventis) 5.1 (ATG5) and 7.5 mg/kg (ATG7.5) administered along with 450 cGy total body irradiation (TBI). This study followed an earlier trial which examined the optimal schedule of ATG administration in this regimen (Toor et al, BMT 2008). ATG was administered from day -9 to day -7, and fractionated TBI on day -1 and 0. Tacrolimus and mycophenolate mofetil were administered for GVHD prophylaxis.

Toor: Genzyme: Research Funding. Off Label Use: ATG in stem cell transplantation.

Abstract 3043

McCarty: Celgene: Honoraria; Genzyme: Honoraria. Toor:Genzyme: Research Funding.

Abstract 4662