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A simple strategy is developed to simultaneously release tensile strain and passivate defects in an FA-based perovskite using CsPbI3 QDs, achieving a PCE of 23.3%.

PDF file - 50KB, Correlation between RPPA and immunoblotting in samples from the patients treated on MK-2206 trial.

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PDF file - 131KB, Effects of MK-2206 on AKT signaling in FLT3-mutant AML cells.

Supplementary Figure 1.Baseline 4EBP1 and outcomes.

Purpose: Previous studies suggest a potential therapeutic role for mTOR inhibition in lymphoid malignancies. This single-center phase I/II study was designed to test the safety and efficacy of the mTOR inhibitor everolimus in combination with HyperCVAD chemotherapy in relapsed/refractory acute lymphoblastic leukemia (ALL).Experimental Design: Twenty-four patients were treated; 15 received everolimus 5 mg/day and 9 received 10 mg/day with HyperCVAD.Results: The median age of patients was 25 years (range, 11–64) and median number of prior treatments was 2 (range, 1–7). Grade 3 mucositis was the dose-limiting toxicity and the maximum tolerated everolimus dose was 5 mg/day. Responses included complete remission (CR) in 6 patients (25%), CR without platelet recovery (CRp) in 1 (4%), and CR without recovery of counts (CRi) in 1 (4%), for an overall response rate of 33%. In addition, partial response (PR) was noted in 2 patients (8%). Seven of 11 patients treated in first salvage achieved CR/CRp (64%). The median OS was 29 weeks for patients in first salvage versus 15 weeks for patients in second salvage and beyond (P ≤ 0.001). A response was noted in 5 of 10 (50%) heavily pretreated T-ALL patients (median of 4 prior salvage regimens). Everolimus significantly inhibited phosphorylation of S6RP, but this did not correlate with response. No significant decreases in p4EBP1 and pAkt levels were noted. Responders had higher everolimus dose-adjusted area under the curve (P = 0.025) and lower clearance (P = 0.025) than nonresponders.Conclusions: The combination of HyperCVAD and everolimus is well tolerated and moderately effective in relapsed ALL, specifically T-ALL. Clin Cancer Res; 21(12); 2704–14. ©2015 AACR.

Supplementary Figure 2. OS and EFS by salvage status.

Supplementary Figure S1. TH-302 has potent antitumor activity in a 3D in vitro co-culture system of leukemia cells and bone marrow-derived mesenchymal stromal cells that recapitulates the multidimensional BM niche Supplementary Figure S2. Hypoxia is present in spheroids as indicated by PIMO positive staining in spheroids incubated with PIMO for 3hr before harvesting Supplementary figure S3. In vitro synergistic activity of TH-302 in combination with chemotherapy and demethylating agents Supplementary Figure S4. TH-302 has anti-leukemia activity in an in vivo primary AML xenograft murine model. Supplementary figure S5. In vitro synergistic activity of TH-302 in combination with sorafenib Supplementary figure S6 A, B. Assessment of BM hypoxia in AML/ETO bearing mice treated with TH-302 or chemotherapy

PDF file - 145KB, The subtraction heat maps of selected markers in paired PB samples.

PDF file - 60KB, MK-2206 promotes accumulation of OCI-AML3 cells in the G1 phase of the cell cycle.

Supplemental Methods and Tables 1) mRNA Hybridization and Gene-expression Profiling. 2) Gene expression analysis by Nanostring technology. 3) Hyperpolarized Magnetic Resonance Spectroscopy. 4) In Vitro 1-13C Pyruvic Acid Feeding Studies and High Resolution Nuclear Magnetic Resonance (NMR) Experiments 5) Three-dimensional spheroids 6) Murine tumor models 7) Immunohistochemistry Supplementary Table S1. Cell line characteristics Supplementary Table S2. Patient characteristics Supplemental Table S3. List of upregulated DEPs in hypoxia. Supplemental Table S4. 1-13C pyruvate uptake and 1-13C lactate production in cell culture. Supplemental Table S5. TH-302 cytotoxic activity against leukemia cell lines

Purpose: To characterize the prevalence of hypoxia in the leukemic bone marrow, its association with metabolic and transcriptional changes in the leukemic blasts and the utility of hypoxia-activated prodrug TH-302 in leukemia models.Experimental Design: Hyperpolarized magnetic resonance spectroscopy was utilized to interrogate the pyruvate metabolism of the bone marrow in the murine acute myeloid leukemia (AML) model. Nanostring technology was used to evaluate a gene set defining a hypoxia signature in leukemic blasts and normal donors. The efficacy of the hypoxia-activated prodrug TH-302 was examined in the in vitro and in vivo leukemia models.Results: Metabolic imaging has demonstrated increased glycolysis in the femur of leukemic mice compared with healthy control mice, suggesting metabolic reprogramming of hypoxic bone marrow niches. Primary leukemic blasts in samples from AML patients overexpressed genes defining a “hypoxia index” compared with samples from normal donors. TH-302 depleted hypoxic cells, prolonged survival of xenograft leukemia models, and reduced the leukemia stem cell pool in vivo. In the aggressive FLT3/ITD MOLM-13 model, combination of TH-302 with tyrosine kinase inhibitor sorafenib had greater antileukemia effects than either drug alone. Importantly, residual leukemic bone marrow cells in a syngeneic AML model remain hypoxic after chemotherapy. In turn, administration of TH-302 following chemotherapy treatment to mice with residual disease prolonged survival, suggesting that this approach may be suitable for eliminating chemotherapy-resistant leukemia cells.Conclusions: These findings implicate a pathogenic role of hypoxia in leukemia maintenance and chemoresistance and demonstrate the feasibility of targeting hypoxic cells by hypoxia cytotoxins. Clin Cancer Res; 22(7); 1687–98. ©2015 AACR.

Purpose: Recent studies suggested that AKT activation might confer poor prognosis in acute myelogenous leukemia (AML), providing the rationale for therapeutic targeting of this signaling pathway. We, therefore, explored the preclinical and clinical anti-AML activity of an oral AKT inhibitor, MK-2206.Experimental Methods: We first studied the effects of MK-2206 in human AML cell lines and primary AML specimens in vitro. Subsequently, we conducted a phase II trial of MK-2206 (200 mg weekly) in adults requiring second salvage therapy for relapsed/refractory AML, and assessed target inhibition via reverse phase protein array (RPPA).Results: In preclinical studies, MK-2206 dose-dependently inhibited growth and induced apoptosis in AML cell lines and primary AML blasts. We then treated 19 patients with MK-2206 but, among 18 evaluable participants, observed only 1 (95% confidence interval, 0%–17%) response (complete remission with incomplete platelet count recovery), leading to early study termination. The most common grade 3/4 drug-related toxicity was a pruritic rash in 6 of 18 patients. Nevertheless, despite the use of MK-2206 at maximum tolerated doses, RPPA analyses indicated only modest decreases in Ser473 AKT (median 28%; range, 12%–45%) and limited inhibition of downstream targets.Conclusions: Although preclinical activity of MK-2206 can be demonstrated, this inhibitor has insufficient clinical antileukemia activity when given alone at tolerated doses, and alternative approaches to block AKT signaling should be explored. Clin Cancer Res; 20(8); 2226–35. ©2014 AACR.

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Supplementary material and methods, Tables 1-3. Supplementary table 1. Changes in the expression of proteins and their phosphorylated forms with everolimus treatment analyzed by RPPA; Supplementary table 2. Results of binomial analysis showing direction of changes in the expression of proteins and their phosphorylated forms, analyzed by RPPA, for individual patients; Supplementary Table 3. Major everolimus pharmacokinetic parameters in cycles 1 and 2a.

A self-assembled nanofibrillar conjugated polymer film is used to optimize the CsPbIBr2/hole-transporting layer interface. The obtained CsPbIBr2 solar cell demonstrates an efficiency of 11.05% with excellent long-term stability.

The thermal protection system (TPS) for spacecraft is easily damaged by various thermal and mechanical loads, which adversely affects the thermal protection performance of the system. TPS damages d...

Building sustainable and affordable transport systems is a key issue for social development and sustainable urban expansion. The study used dynamic ordinary least squares (DOLS) and fully modified ordinary least squares (FMOLS) to examine the impact of transport infrastructure investment on environmental degradation in China, Japan, and South Korea over the period 1995–2020 and the validity of the EKC hypothesis. The results show that GDP has a significant positive effect, and GDP2 and GDP3 have significant adverse effects on environmental degradation, respectively. These results confirm the validity of the inverted U shaped EKC hypothesis in selected Asian countries. Road infrastructure investment has a significant positive effect, while railway infrastructure investment has a significant adverse effect on environmental degradation. Air infrastructure investment and trade opening have a progressive and statistically significant impact on environmental pollution. Modern rail systems that run on electricity are considered less polluting, so the share of rail infrastructure investment in the transport mix can help build sustainable and safe transport systems at the city Centre and intercity levels and reduce emissions in Asian countries. Moreover, strict enforcement of the prevailing environmental conditions of trade agreements should be encouraged to reduce the increasing impact of free trade on environmental pollution.

A terahertz phase shifter based on liquid-crystal-integrated metasurface is proposed, which contains a three-slotted array structure and comb grating. The orientation of the liquid crystal molecules can be completely controlled by the direction of the electric field. From the acquired experimental results, it was demonstrated that the phase shift exceeds 300° in the range of 378.6 - 390.8 GHz, whereas the maximum phase shift reaches 374.1° at 383.1 GHz. The molecular reorientation transient process induced by the external electric field in the liquid crystal was measured and analyzed. Based on the molecular reorientation mechanism, which can be divided into three processes, a rapid modulation mechanism was demonstrated. From the performance of the proposed device, an actively controllable phase delay and reflectance with a cycle switching time of approximately 0.3 s was achieved, which is remarkably faster than the usual cycle time that exceeds 8 s. Our work provides useful ideas for improving the response speed of LC-based terahertz devices, which is considered of great significance for several applications, in terms of terahertz reconfigurable devices.

A tunable metasurface absorber (MA) based on polymer network liquid crystal is introduced in this paper. Despite the well-designed unit cell patterns, the proposed MA can achieve both large frequency tunability and wide-angle stability. Compared with traditional liquid crystal-based metasurfaces, the measured results suggest that the recovery time of the proposed structure was reduced by half. By applying an external voltage on the top electrode of the liquid crystal layer from 0 to a saturation voltage of 10 V, the absorption peak of the MA can be tuned from 112.7 GHz to 102.2 GHz, with a maximum frequency tunability of 9.3%, which is significantly higher than other proposed liquid crystal-based metasurfaces. Moreover, the proposed tunable absorber can maintain absorption greater than 90% with incident angles reaching up to 60° for both transverse electric and transverse magnetic polarizations. This design provides an efficient way for developing low-power consumption terahertz devices with large frequency tunability and wide-angle stability.

In this study, a facile method was developed for the fabrication of liquid crystal (LC) polarisation converter arrays. To this end, arrays of LC droplets were first formed self-assembly by scribing...

In this report, an LCMLA with a negative-positive tunable focal length is designed using a self-assembled highly uniform polymer convex array. The polymer convex array was prepared by scribing UV-s...

This letter presented a nematic liquid crystal (LC) based metal-dielectric-metal structure to fully electronically modulate the reflection phase of electromagnetic waves. The demonstrated structure is composed of a thin LC layer sandwiched between copper comb electrodes and a single slotted reflection array. Based on a proper application of the external electric field, the whole process of nematic LC molecular orientation is controlled. The innovative feeding method can actively prealign and deflect the orientation of LC molecules. Experimental results show that the maximum reflection phase shift is 189.2° at 114.9 GHz. This letter provides a practical way of regulating LC-based terahertz devices. The proposed structure is a potential candidate for the reconfigurable reflectarray antennas.

High enthalpy stagnation gas can be converted into hypervelocity flow through the contraction—expansion nozzle. The enthalpy flow in the nozzle can be divided into three regions: an equilibrium region, a non-equilibrium region, and a frozen region. The stagnation gas with a total enthalpy of 13.4 MJ/kg is used to analyze the thermochemical non-equilibrium effects. At the selected conditions, the effects of a conical nozzle under different expansion angles of the expansion section, curvature radius of the throat, throat radius, and convergence angle of the convergent section are investigated. Based on the Spalart–Allmaras one-equation turbulence model with the Catris–Aupiox compressibility correction, a multi-block solver for axisymmetric compressible Navier–Stokes equations is applied to simulate the thermochemical non-equilibrium flow in several high enthalpy conical nozzles. The multi-species two-temperature equation is employed in the calculation. The results reveal three interesting characteristics: Firstly, the thermochemical non-equilibrium effects are sensitive to the maximum expansion angle and throat radius but not to the radius of throat curvature and contraction angle. Secondly, as the maximum expansion angle decreases and the throat radius increases, the flow approaches equilibrium state. When the maximum expansion angle decreases from 12° to 4°, the freezing temperature decreases from 2623 K to 2018 K. When the throat diameter increased from 10 mm to 30 mm, the freezing temperature decreased from 2442 K to 2140 K. Finally, the maximum expansion angle and throat radius not only affect the position of the freezing point but also the flow field parameters, such as temperature, Mach number, and species mass fraction.

Both random laser and multimode band-edge laser have been found in cholesteric liquid crystals (CLCs). In this work, the laser emission in CLC with negative dielectric anisotropy under electric fie...

A liquid crystal microlens array (LCMLA) with positive and negative focal lengths based on a ring-array patterned electrodes is demonstrated. By carefully designing patterned electrodes with a circular electrode array area and outer ring electrode region area, the switching of the positive and negative lens effect can be easily achieved in a single cell. A positive lens effect appeared when the voltage was applied to the outer ring electrode region and the top substrate. The focal length changed from infinity to 1 mm as the voltage varied from 0 to 3 V r m s . A negative lens effect occurred when the voltage was applied to the circular electrode array and the top substrate. The focal length varied from infinity to − 1 m m when the voltage changed from 0 to 2 V r m s . The imaging properties of the LCMLA at different voltages are evaluated. Our LCMLA, with simple structure, low driving voltage, and good stability, has potential applications in optical communication, imaging processing, and displays.

Although many studies on cholesteric liquid crystal (CLC) microdroplet single-mode lasers are available, it has been shown that the stability and tunability of such microdroplets are difficult to achieve simultaneously. In this paper, a new, to the best of our knowledge, method is proposed for the mass and rapid preparation of stable and tunable monodisperse CLC microdroplet single-mode lasers. This is based on the formation of polymer networks on the surface of the microdroplet via interfacial polymerization and a disruption of the orderliness of the polymer networks by increasing the temperature during polymerization, which results in a single pitch inside the microdroplets. This approach enables CLC microdroplet single-mode lasers to achieve improved environmental robustness, while maintaining the same temperature tunability as the unpolymerized sample. Our method has promising future applications in integrated optics, flexible devices, and sensors.

Growing malignant tumors must evade destruction by the immune system, a hurdle some malignancies overcome by attracting immune-suppressive regulatory T-cells (Tregs)1. The IKZF2 (Helios) transcription factor plays a crucial role in maintaining function and stability of Tregs, and IKZF2 deficiency enhances immune responses to tumors in mice2, suggesting IKZF2 may be an attractive target for cancer immunotherapy. Here we describe the discovery and characterization of DKY709, the first molecular glue degrader of IKZF2/4 which spares IKZF1/3. DKY709 was identified through a recruitment-guided medicinal chemistry campaign that redirected the degradation selectivity of CRBN binders towards IKZF2. The IKZF transcription factor selectivity of DKY709 was rationalized by the X-ray structure of the CRBN-DKY709-IKZF2(ZF2) ternary complex. Upon exposure to DKY709, human Tregs showed reduced suppressive activity and exhausted T-effector cells recovered IFNγ production. In vivo, oral treatment with DKY709 drove a rapid and sustained degradation of IKZF2 including in humans and led to delayed tumor growth in mice with humanized immune systems and enhanced immunization responses in monkeys. DKY709 is a first-in-class, potent and selective oral IKZF2/4 degrader currently being investigated in a phase 1 clinical trial as an immune-enhancing agent for cancer immunotherapy.

In this work, the agglomeration, fragmentation, and separation process of coarse-grained pulverized coal agglomerates (CGPCA) obtained from a power plant were achieved using gas-solid fluidized bed sorting and analyzed through a combination of numerical simulations and actual experiments with CGPCA. To study the polydispersity and irregularity of CGPCA, the CGPCA surface fractal dimension was calculated using fractal dimension combined with scanning electron microscopy. The two-section fractal dimension of the particle size distribution was obtained by fitting the logarithmic particle size distribution of CGPCA. On the basis of the obtained data, the polydisperse particle drag force model, the agglomeration kernel function, and the breakage kernel function were modified. Thus, an irregular polydisperse gas-solid two-phase Eulerian-Eulerian model was constructed to simulate the sorting process of CGPCA in the fluidized bed. The results of the numerical simulation investigation were compared with the experimental results and showed that the simulation data, which considered the two section fractal dimension, was in better agreement with the experimental results. The cumulative logarithmic distribution of CGPCA's size was segmented and fitted. The values of the two section fractals of the agglomerates were determined as

In this study, low driving voltage liquid crystal microlens array (LCMLA) based on polyvinyl alcohol (PVA) convex array was fabricated by facile method. The PVA convex array served as a vertical al...

Electrically tunable random laser action has been demonstrated in a cavity-free structure. The scattering structure was shaped by the treatment of AC, and a polymer network structure is introduced ...

A liquid crystal (LC)-based double dipole terahertz phase shifter is proposed. The block model is utilized in simulations to analysis the influence of inhomogeneity of the LC substrate. The sensitive parameters of the double dipole are simulated and analyzed. An array consisting of 30 × 30 patch elements is designed and fabricated. Experimental results exhibit that the phase shift is over 360° in the range of 355.8–358.8 GHz at 1 kHz, at an applied AC bias in the 0–50 V range. The phase change at different frequencies of AC bias voltage is also investigated, and the effect of the frequency of AC bias voltage is expressed by the coefficient of the amplitude of the bias voltage.

Unipolar n-type conjugated polymer materials with long-term stable electron transport upon direct exposure to the air atmosphere are very challenging to prepare. In this study, three unipolar n-type donor-acceptor (D-A) conjugated polymer semiconductors (abbreviated as PNVB, PBABDFV, and PBAIDV) were successfully developed through a "strong acceptor-weak donor" strategy. The weak electron donation of the donor units in all three polymers successfully lowered the molecular energy levels by the acceptor units that strongly attracted electrons. Cyclic voltammetry demonstrated that all three polymers had low highest occupied molecular orbital and lowest unoccupied molecular orbital energy levels near -6.0 and -4.0 eV, respectively. These results were consistent with the density functional theory calculations. The as-prepared polymers were then used to manufacture organic field-effect transistor (OFET) devices in bottom-gate/top-contact (BG/TC) configuration without any packaging protection. As expected, all devices exhibited unipolar electron transport properties. PBABDFV-based devices showed excellent field-effect performance and air stability, beneficial for straight-line molecular chain and closest π-π stacking distance to prevent water vapor and oxygen from diffusion into the active layer. This led to a maximum electron mobility (μe,max) of 0.79 cm2 V-1 s-1 under air conditions. In addition, 0.50 cm2 V-1 s-1 was still maintained after 27 days of storage in ambient environment. The near-ideal transfer curve of the PBABDFV-based OFET device in BG/TC configuration under vacuum was obtained with average mobility reliability factor (rave) reaching 88%.