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Electromagnetic metamaterial absorbers (MMAs), with pivotal roles in applications such as stealth and communication, have revolutionised the field of absorbing materials by offering unique characteristics unattainable by natural materials through artificially designed unit cell structures. Although many MMAs have been successfully prepared through traditional micro/nano fabrication processes, inherent limitations persist. 3D printing, or additive manufacturing, offers unprecedented design freedom and streamlined production processes for MMAs. This review provides a comprehensive examination of 3D-printed MMAs. It first introduces the fundamental concepts and history of MMAs with a brief description of traditional techniques for MMA fabrication. Subsequently, it elucidates mechanisms governing the loss and absorption of electromagnetic MMAs and traditional absorbing materials, shedding light on the design principles. Next, this review centres on 3D printing modalities employed to fabricate MMAs by categorising the processes into one-step and two-step manufacturing that leverage the unique advantages of 3D printing. Moreover, it also delves into innovative 4D-printed MMAs, showcasing the potential of dynamically adjustable MMAs. In the end, potential future research directions are discussed by taking into consideration of current concerns. This review underscores the transformative impact of 3D-printed MMAs, paving a new avenue for future innovations in electromagnetic engineering.

We have simulatively studied the electrical excitation of acoustic and optical plasmons in double-channel AlGaN/GaN high electron mobility transistors (HEMT) under asymmetric boundaries. By solving the self-consistent hydrodynamic model with Maxwell’s equations, it is found that the drift plasmons are excited in the bilayer 2DEGs under asymmetric boundaries. The oscillation intensity in a bilayer system is much stronger than that in a monolayer 2DEG system because of the simultaneous excitation of the fundamental and the second harmonic components. The fundamental component always corresponds to the acoustic plasmon, while the optical plasmon can be excited when it is resonant with the second harmonic of the acoustic plasmon. Because of the out-of-phase properties of the acoustic plasmons, their radiated power is limited by the current cancellation. On the other hand, as the optical plasmons are excited, the radiated powers are much higher than those of the single channel HEMT due to the in-phase currents generated in the double layers. The effects of different parameters such as gate lengths, 2DEG spacings, and electron concentrations on plasmon excitations and THz emissions of double-channel HEMTs are analyzed in detail. The numerical results provide a more powerful terahertz radiation mechanism in double-channel HEMT compared with the Dyakonov–Shur instability in traditional single-channel HEMT.

Entanglement is one of the most striking features of quantum systems, whereby its non-classical correlation is an essential resource in numerous quantum protocols. Entanglement can be divided into two categories: interparticle and intraparticle entanglement. There are both distinctions and similarities between these two kinds of entangled states. This work delves into these distinctions and similarities from the following aspects: correlation and non-locality, robustness, the mechanisms of generation and separation, and practical applications. Entanglement swapping is a technique based on quantum entanglement. As entanglement has different categories, entanglement swapping also has various types, including interparticle to interparticle and intraparticle to interparticle. Swapping protocols from intraparticle entanglement to interparticle entanglement can be applied to super quantum dense encoding, quantum information transmission, quantum teleportation, etc. Thus, this work proposes three swapping protocols, from spin–orbit intraparticle entanglement to spin–spin interparticle entanglement, based on Bell state joint measurement, the cross-Kerr medium, and linear optical elements. This work can help us better understand entanglement by analyzing the differences and similarities between the two types of entangled states. It can also enhance entanglement swapping protocols, from spin–orbit intraparticle to spin–spin interparticle entanglement, for use in quantum information transfer.

For the purpose of improving performance and reducing the fabrication difficulty of terahertz traveling wave tubes (TWTs), this paper proposes a novel single-section high-gain slow wave structure (SWS), which is named the symmetrical quasi-synchronous step-transition (SQSST) folded waveguide (FW). The SQSST-FW SWS has an artificially designed quasi-synchronous region (QSR) to suppress self-oscillations for sustaining a high gain in an untruncated circuit. Simultaneously, a symmetrical design can improve the efficiency performance to some extent. A prototype of the SQSST-FW SWS for 650 GHz TWTs is designed based on small-signal analysis and numerical simulation. The simulation results indicate that the maximum saturation gain of the designed 650 GHz SQSST-FW TWT is 39.1 dB in a 34.3 mm slow wave circuit, occurring at the 645 GHz point when a 25.4 kV 15 mA electron beam and a 0.43 mW sinusoidal input signal are applied. In addition, a maximum output power exceeding 4 W is observed at the 648 GHz point using the same beam with an increased input power of around 2.8 mW.

Abstract Loss of the tumor suppressive activity of the protein phosphatase 2A (PP2A) is associated with cancer, but the underlying molecular mechanisms are unclear. PP2A holoenzyme comprises a heterodimeric core, a scaffolding A subunit and a catalytic C subunit, and one of over 20 distinct substrate-directing regulatory B subunits. Methylation of the C subunit regulates PP2A heterotrimerization, affecting B subunit binding and substrate specificity. Here, we report that the leucine carboxy methyltransferase (LCMT1), which methylates the L309 residue of the C subunit, acts as a suppressor of androgen receptor (AR) addicted prostate cancer (PCa). Decreased methyl-PP2A-C levels in prostate tumors is associated with biochemical recurrence and metastasis. Silencing LCMT1 increases AR activity and promotes castration-resistant prostate cancer growth. LCMT1-dependent methyl-sensitive AB56αCme heterotrimers target AR and its critical coactivator MED1 for dephosphorylation, resulting in the eviction of the AR-MED1 complex from chromatin and loss of target gene expression. Mechanistically, LCMT1 is regulated by S6K1-mediated phosphorylation-induced degradation requiring the β-TRCP, leading to acquired resistance to anti-androgens. Finally, feedforward stabilization of LCMT1 by small molecule activator of phosphatase (SMAP) results in attenuation of AR-signaling and tumor growth inhibition in anti-androgen refractory PCa. These findings highlight methyl-PP2A-C as a prognostic marker and that the loss of LCMT1 is a major determinant in AR-addicted PCa, suggesting therapeutic potential for AR degraders or PP2A modulators in prostate cancer treatment.

A staggered vane-shaped slot-line slow-wave structure (SV-SL SWS) for application in W-band traveling wave tubes (TWTs) is proposed in this article. In contrast to the conventional slot-line SWSs with dielectric substrates, the proposed SWS consists only of a thin metal sheet inscribed with periodic grooves and two half-metal enclosures, which means it can be easily manufactured and assembled and has the potential for mass production. This SWS not only solves the problem of the dielectric loading effect but also improves the heat dissipation capability of such structures. Meanwhile, the SWS design presented here covers a −15 dB S11 frequency range from 87.5 to 95 GHz. The 3-D simulation for a TWT based on the suggested SWS is also investigated. Under dual-electron injection conditions with a total voltage of 17.2 kV and a total current of 0.3 A, the maximum output power at 90 GHz is 200 W, with a 3 dB bandwidth up to 4 GHz. With a good potential for fabrication using microfabrication techniques, this structure can be a good candidate for millimeter-wave TWT applications.

Surface plasmon polaritons (SPPs) have become a research hotspot due to their high intensity and subwavelength localization. Through free-electron excitation, a portion of the momentum of moving electrons can be converted into SPPs. Converting highly localized SPPs into a radiated field is an approach with the potential to aid in the development of a light radiation source. Reducing losses of SPPs is currently a critical challenge that needs to be addressed. The lifetime of SPPs in metal films is longer than that in metal blocks. Traditional optical gratings can transform SPPs into radiation to avoid the decay of SPPs in metal; however, they are created by etching metal films, so they tend to alter the dispersion characteristics of these films and will emit radiation in the direction perpendicular to the metal surface. This paper proposes an approach to converting the SPPs of a metal film excited by free electrons into a radiation field via lateral grating and obtaining in-plane radiation. We investigate the properties of SPP lateral radiation. The study of lateral radiation from metal films holds significant importance for SPP radiation sources and SPP on-chip circuit development.

The existing end-to-end (E2E) wireless communication systems require fewer communication modules and have a simple processing signal flow, compared to conventional wireless communication systems. However, in the absence of a differentiable channel model, it is impossible to train transmitters, used in such systems, which makes impossible achieving optimal system performance. To solve this problem, E2E wireless communication systems, learned with conditional generative adversarial networks (CGANs) for channel modeling, have been proposed recently. Unfortunately, the CGAN training is prone to instability, slow convergence, and inaccurate channel modeling, which affects the system performance. To this end, a learning-based E2E wireless communication system, utilizing a deep neural network (DNN) channel module to model an unknown channel, is proposed in this paper. Simulation results show that the proposed DNN channel modeling has faster convergence, simpler network structure, and can reflect the behavior of real channels more accurately. In addition, the proposed learning-based E2E wireless communication system performs better, in terms of the bit error rate (BER) and block error rate (BLER), than the learning-based E2E wireless communication system, using CGAN as unknown channel, and a traditional communication system, designed based on the prior knowledge of the channel. Compared to these two systems, at high signal-to-noise ratio (SNR) values, the proposed system can achieve a SNR gain of at least 2 dB, in communication scenarios involving frequency-selective multi-path channels.

Summary: Intermolecular interactions, including hydrogen bonds, dominate the pairing and unpairing of nucleic acid chains in the transfer process of genetic information. The energy of THz waves just matches with the weak interactions, so THz waves may interact with biomolecules. Here, the dynamic effects of THz electromagnetic (EM) waves on the mechanical unfolding process of RNA hairpins (WT-30nt and its mutants, rHP, SARS-CoV-2, and SRV-1 SF206) are investigated using steered molecular dynamics (SMD) simulations. The results show that THz waves can either promote the unfolding of the double helix of the RNA hairpin during the initial unfolding phase (4–21.8 THz) or significantly enhance (23.8 and 25.5 THz) or weaken (37.4 and 41.2 THz) its structural stability during unfolding. Our findings have important implications for applying THz waves to regulate dynamic deconvolution processes, such as gene replication, transcription, and translation.

Excessive expansion of cholangiocytes in the liver leads to ductular reaction and liver disease. Here, the authors show that genetic ablation, or pharmacological inhibition, of biliary NIK blocks ductular reaction, liver inflammation, and liver fibrosis in mice by modulating secretion of cholangiokines that mediate liver inflammation and fibrosis.

Abstract Background Tyrosine kinase inhibitors (TKIs) are mainstays of cancer treatment. However, their clinical benefits are often constrained by acquired resistance. To overcome such outcomes, we have rationally engineered APG-2449 as a novel multikinase inhibitor that is highly potent against oncogenic alterations of anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 receptor tyrosine kinase (ROS1), and focal adhesion kinase (FAK). Here we present the preclinical evaluation of APG-2449, which exhibits antiproliferative activity in cells carrying ALK fusion or secondary mutations. Methods KINOMEscan® and LANCE TR-FRET were used to characterize targets and selectivity of APG-2449. Water-soluble tetrazolium salt (WST-8) viability assay and xenograft tumorigenicity were employed to evaluate therapeutic efficacy of monotherapy or drug combination in preclinical models of solid tumors. Western blot, pharmacokinetic, and flow cytometry analyses, as well as RNA sequencing were used to explore pharmacokinetic–pharmacodynamic correlations and the mechanism of actions driving drug combination synergy. Results In mice bearing wild-type or ALK/ROS1-mutant non-small-cell lung cancer (NSCLC), APG-2449 demonstrates potent antitumor activity, with correlations between pharmacokinetics and pharmacodynamics in vivo. Through FAK inhibition, APG-2449 sensitizes ovarian xenograft tumors to paclitaxel by reducing CD44+ and aldehyde dehydrogenase 1-positive (ALDH1+) cancer stem cell populations, including ovarian tumors insensitive to carboplatin. In epidermal growth factor receptor (EGFR)-mutated NSCLC xenograft models, APG-2449 enhances EGFR TKI-induced tumor growth inhibition, while the ternary combination of APG-2449 with EGFR (osimertinib) and mitogen-activated extracellular signal-regulated kinase (MEK; trametinib) inhibitors overcomes osimertinib resistance. Mechanistically, phosphorylation of ALK, ROS1, and FAK, as well as their downstream components, is effectively inhibited by APG-2449. Conclusions Taken together, our studies demonstrate that APG-2449 exerts potent and durable antitumor activity in human NSCLC and ovarian tumor models when administered alone or in combination with other therapies. A phase 1 clinical trial has been initiated to evaluate the safety and preliminary efficacy of APG-2449 in patients with advanced solid tumors, including ALK + NSCLC refractory to earlier-generation ALK inhibitors. Trial registration Clinicaltrial.gov registration: NCT03917043 (date of first registration, 16/04/2019) and Chinese clinical trial registration: CTR20190468 (date of first registration, 09/04/2019).

How terahertz signals perform in the neural system has attracted widespread interest in the life sciences community. Relevant experimental reveals that in animal nerve cells, the myelin sheath of the nerve axon has a higher refractive index than the intracellular and extracellular fluids in the Terahertz-far-infrared (THz-FIR) frequency band. This makes THz-FIR wave transmission possible in nerve fibers. Based on this premise, this article carries out the following work from the theoretical level to investigate the electromagnetic (EM) characteristics of in vivo nerve fibers at the THz-FIR band. First, the EM transmission model of the nerve fibers is established and studied theoretically. The dispersion curves of THz-FIR wave modals transmission in nerve fibers are calculated, which predict that nerve fibers can act as dielectric waveguides for transmitting THz-FIR waves and the THz-FIR waves can transmit at speeds up to 108 m/s. Second, a mode matching algorithm is proposed, which is named RNMMA, to calculate the transmission characteristics of THz-FIR waves at the nodes of Ranvier. The scattering matrix obtained from the proposed algorithm is in good agreement with the results from EM simulation software, which reveals how THz-FIR signals are transmitted forward through the nodes of Ranvier with low loss.

Smith–Purcell radiation (SPR) is a phenomenon in that free electrons moving above a periodic structure deliver a part of their kinetic energies to electromagnetic waves. It plays an important role in the development of radiation sources and beam diagnosis. With the development of nanofabrication technology, various complex micro‐nano‐metallic periodic or aperiodic structures have been adopted to improve the efficiency and coherence of SPR. In general, when free electrons move above the metallic periodic structure, the localized surface wave and Smith–Purcell radiation wave are excited simultaneously. As the frequency of the surface wave is always lower than the threshold of Smith–Purcell radiation, the surface wave cannot be radiated. Here, the surface wave is transformed into SPR by using a novel composite subwavelength hole array, thus the SPR is enhanced and it becomes coherent and easy to tune. This work provides a competitive approach to achieve a coherent and high‐efficiency THz radiation source.

The fundamental unit for comprehending the physicochemical properties of water, the Zundel cation configuration H5O2+, has yet to be exhaustively evaluated in terms of its interaction with terahertz (THz) electromagnetic waves, characterized by sub-picosecond oscillation periods or pulse widths. In this study, we embark on an investigation of the broad resonance and high-field nonresonant effects of intense THz radiation (ITR) on Zundel cations, utilizing a multifaceted methodological approach that includes density functional theory (DFT) calculations, finite difference time domain (FDTD) algorithm of the Schrödinger equation, and ab initio molecular dynamics (AIMD) simulations. Our analysis reveals that the proton potential energy surface (PES) varies in response to the external electric (E) field, suggesting that the interaction frequency of the central proton with the electromagnetic wave encompasses the THz band. This resonance effect is associated with proton behavior that may oscillate or demonstrate periodic tunneling. Moreover, our work uncovers the high-field nonresonant effects of ITR on Zundel cations, manifesting in proton transfer and vibrational excitation of the system. Our findings contribute to the understanding of the interaction between Zundel species and electromagnetic waves by presenting a microscopic view of proton transfer as informed by wavefunction evolution.

New treatment options, such as targeted therapies, are urgently needed for the treatment of colorectal cancer (CRC), the third leading cause of cancer-related deaths worldwide. The current study focuses on demonstrating the therapeutic efficacies of APG-1252-M1 (an active form of the prodrug, APG-1252 or pelcitoclax), a highly potent Bcl-2/Bcl-XL dual inhibitor in clinical trials, against CRC and understanding the underlying mechanisms. APG-1252-M1 effectively decreased the survival of CRC cell lines, particularly those expressing relatively low levels of Mcl-1, with the induction of apoptosis. High levels of Mcl-1 were significantly correlated with decreased sensitivity of CRC cell lines to APG-1252-M1. When combined with an Mcl-1 inhibitor, APG-1252-M1 synergistically decreased the survival and induced apoptosis of APG-1252-M1-insensitive cell lines with high levels of Mcl-1. This combination further decreased the survival and enhanced apoptosis even in sensitive cell lines with relatively low levels of Mcl-1, whereas enforced expression of ectopic Mcl-1 in these cells abrogated APG-1252-M1’s effects on decreasing cell survival and inducing apoptosis, which could be reversed by Mcl-1 inhibition. APG-1252-M1 rapidly induced cytochrome C and Smac release from mitochondria with caspase-3 and PARP cleavage. Deficiency of Bax in CRC cells abolished APG-1252-M1’s ability to induce apoptosis, indicating that APG-1252-M1 induces Bax-dependent apoptosis. The current study thus demonstrates the potential of APG-1252-M1 as a monotherapy in the treatment of CRC, particularly those with low Mcl-1 expression, or in combination with an Mcl-1 inhibitor, warranting further evaluation in vivo and in the clinic.

Activation of cullin-RING ligases can be inhibited by targeting DCN1, but selective DCN1 inhibitors with in vivo activity are lacking. Here, the authors develop covalent DCN1 inhibitors that selectively and potently inhibit cullin-3 activation and downstream functions in cells and in mice.

In this paper, a novel staggered double-segmented grating slow-wave structure (SDSG-SWS) is developed for wide-band high-power submillimeter wave traveling-wave tubes (TWTs). The SDSG-SWS can be considered as a combination of the sine waveguide (SW) SWS and the staggered double-grating (SDG) SWS; that is, it is obtained by introducing the rectangular geometric ridges of the SDG-SWS into the SW-SWS. Thus, the SDSG-SWS has the advantages of the wide operating band, high interaction impedance, low ohmic loss, low reflection, and ease of fabrication. The analysis for high-frequency characteristics shows that, compared with the SW-SWS, the SDSG-SWS has higher interaction impedance when their dispersions are at the same level, while the ohmic loss for the two SWSs remains basically unchanged. Furthermore, the calculation results of beam–wave interaction show that the output power is above 16.4 W for the TWT using the SDSG-SWS in the range of 316 GHz–405 GHz with a maximum power of 32.8 W occurring at 340 GHz, whose corresponding maximum electron efficiency is 2.84%, when the operating voltage is 19.2 kV and the current is 60 mA.

The androgen receptor (AR) has been found to be expressed in the majority of human breast cancer and AR antagonists, such as enzalutamide, have shown promising clinical activity in AR-positive (AR+) breast cancer. We have recently reported the discovery of a highly potent PROTAC AR degrader, ARD-61. In this study, we evaluated ARD-61 for its therapeutic potential and mechanism of action in breast cancer models in vitro and in vivo. ARD-61 potently and effectively induces AR degradation in AR+ breast cancer cell lines and is much more potent than enzalutamide in inhibition of cell growth and induction of cell cycle arrest and/or apoptosis. ARD-61 effectively induces complete AR degradation in xenograft tumor tissue and is more effective than enzalutamide in achieving tumor growth inhibition in the MDA-MB-453 xenograft model in mice. Our study provides strong preclinical rationale to develop AR degraders for the treatment of AR+ human breast cancer.

Androgen receptor (AR) antagonists, such as enzalutamide, have had a major impact on the treatment of metastatic castration-resistant prostate cancer (CRPC). However, even with the advent of AR antagonist therapies, patients continue to develop resistance, and new strategies to combat continued AR signalling are needed. Here, we develop AR degraders using PROteolysis TArgeting Chimeric (PROTAC) technology in order to determine whether depletion of AR protein can overcome mechanisms of resistance commonly associated with current AR-targeting therapies. ARD-61 is the most potent of the AR degraders and effectively induces on-target AR degradation with a mechanism consistent with the PROTAC design. Compared to clinically-approved AR antagonists, administration of ARD-61 in vitro and in vivo results in more potent anti-proliferative, pro-apoptotic effects and attenuation of downstream AR target gene expression in prostate cancer cells. Importantly, we demonstrate that ARD-61 functions in enzalutamide-resistant model systems, characterized by diverse proposed mechanisms of resistance that include AR amplification/overexpression, AR mutation, and expression of AR splice variants, such as AR-V7. While AR degraders are unable to bind and degrade AR-V7, they continue to inhibit tumor cell growth in models overexpressing AR-V7. To further explore this, we developed several isogenic prostate cell line models in which AR-V7 is highly expressed, which also failed to influence the cell inhibitory effects of AR degraders, suggesting that AR-V7 is not a functional resistance mechanism for AR antagonism. These data provide compelling evidence that full-length AR remains a prominent oncogenic driver of prostate cancers which have developed resistance to AR antagonists and highlight the clinical potential of AR degraders for treatment of CRPC.

Summary: The question of whether terahertz (THz) waves can interact with ions in channels of nerve cells and cause a further reaction has attracted much attention. To answer this question, we investigate the spontaneous radiation generated by Ca2+ moving in calcium channels and the effect of THz radiation on the transport of Ca2+ by solving the mathematical physical model through Brownian dynamics (BD) simulations. It is obtained that the moving Ca2+ in a calcium channel can generate electromagnetic radiation, the corresponding spectrum of which is concentrated in the THz range. Meanwhile, both the ion number in the channel and the background temperature are proved to have significant effects on the spontaneous emission spectra. The studies also show that external THz radiation can accelerate Ca2+ transport through the ion channel. These results are expected to provide a theoretical basis for the future treatment of THz waves in the neurological field.

In this paper, an angular radial extended interaction amplifier (AREIA) that consists of a pair of angular extended interaction cavities is proposed. Both the convergence angle cavity and the divergence angle cavity, which are designed for the converging beam and diverging beam, respectively, are investigated to present the potential of the proposed AREIA. They are proposed and explored to improve the beam–wave interaction capability of W-band extended interaction klystrons (EIKs). Compared to conventional radial cavities, the angular cavities have greatly decreased the ohmic loss area and increased the characteristic impedance. Compared to the sheet beam (0°) cavity, it has been found that the convergence angle cavity has a higher effective impedance and the diverging beam has a weaker space-charge effect under the same ideal electron beam area; the advantages become more obvious as the propagation distance increases. Particle-in-cell (PIC) results have shown that the diverging beam (8°) EIA performs better at an output power of 94 GHz under the condition of lossless, while the converging beam (−2°) EIA has a higher output power of 6.24 kW under the conditions of ohmic loss, an input power of 0.5 W, and an ideal electron beam of 20.5 kV and 1.5 A. When the loss increases and the beam current decreases, the output power of the −2° EIA can be improved by nearly 30% compared to the 0° EIA, and the −2° EIA has a greatly improved beam–wave interaction capacity than conventional EIAs under those conditions. In addition, an angular radial electron gun is designed.

The p53 protein has appropriately been named the “guardian of the genome”. In almost all human cancers, the powerful tumor suppressor function of p53 is compromised by a variety of mechanisms, including mutations with either loss of function or gain of function and inhibition by its negative regulators MDM2 and/or MDMX. We review herein the progress made on different therapeutic strategies for targeting p53.

Studies on the efficacy of small molecule inhibitors in Merkel cell carcinoma (MCC) have been limited and largely inconclusive. In this study, we investigated the therapeutic potential of a potent BET degrader, BETd-246, in the treatment of MCC. We found that MCC cell lines were significantly more sensitive to BETd-246 than to BET inhibitor treatment. Therapeutic targeting of BET proteins resulted in a loss of “MCC signature” genes but not MYC expression as previously described irrespective of Merkel cell polyomavirus (MCPyV) status. In MCPyV+ MCC cells, BETd-246 alone suppressed downstream targets in the MCPyV-LT Ag axis. We also found enrichment of HOX and cell cycle genes in MCPyV− MCC cell lines that were intrinsically resistant to BETd-246. Our findings uncover a requirement for BET proteins in maintaining MCC lineage identity and point to the potential utility of BET degraders for treating MCC.

A novel electron-optical system is proposed for dual azimuthally stacked radial sheet electron beams (ARSEBs). The two sheet beams are emitted from curved surfaces of two cathodes and are focused by a focusing electrode, which is carefully designed to produce a symmetric field distribution for the two beams and to avoid interference between the beams. A common tunable periodic cusped magnetic focusing system is also designed to focus the two ARSEBs. The dual sheet beams are used in a traveling wave tube (TWT) consisting of a cascade of two azimuthally supported angular log-periodic strip-line (ASALS) slow-wave structures (SWSs). The transmission efficiency in the presence of beam–wave interaction is 93%. The particle-in-cell simulation results show that for a beam voltage of 4400 V and a current of 0.39 A, the proposed cascaded TWT has a maximum gain of 32.5 dB at 35 GHz and a maximum output power of 180 W; this is a significant gain improvement over a TWT using a single ASALS SWS.

A terahertz metamaterial sensor for thin film sensing is proposed and investigated by a numerical study. The designed metamaterial sensor consists of an array of back to back c-shaped double-gap resonators, which can be obtained by simple manufacturing processes. By checking the shift of the resonate frequency of the sensor, the thickness of the analytes deposited on the sensor surface can be identified. We analyzed the sensitivities and corresponding quality factors of the sensor excited by two orthogonal polarized terahertz waves individually for both loss-free and lossy coating analyte layers. The electric field distributions of the metamaterial sensor with different analyte thicknesses are analyzed in detail to illustrate the principle of thin film detection and the principle of improving sensitivity. The transmission line model is built to verify the results of the numerical simulation. This study provides a useful reference for the design of biosensors based on metamaterial sensors in the future.

Streptococcus pneumoniae is well known for phase variation between opaque (O) and transparent (T) colonies within clonal populations. While the O variant is specialized in invasive infection (with a thicker capsule and higher resistance to host clearance), the T counterpart possesses a relatively thinner capsule and thereby higher airway adherence and colonization. Our previous study found that phase variation is caused by reversible switches of the "opaque ON-or-OFF" methylomes or methylation patterns of pneumococcal genome, which is dominantly driven by the PsrA-catalyzed inversions of the DNA methyltransferase hsdS genes. This study revealed that switch frequency between the O and T variants is regulated by five transcriptional response regulators (rr) of the two-component systems (TCSs). The mutants of rr06, rr08, rr09, rr11 and rr14 produced significantly fewer O and more T colonies. Further mutagenesis revealed that RR06, RR08, RR09 and RR11 enrich the O variant by modulating the directions of the PsrA-catalyzed inversion reactions. In contrast, the impact of RR14 (RitR) on phase variation is independent of PsrA. Consistently, SMRT sequencing uncovered significantly diminished "opaque ON" methylome in the mutants of rr06, rr08, rr09 and rr11 but not that of rr14. Lastly, the phosphorylated form of RR11 was shown to activate the transcription of comW and two sugar utilization systems that are necessary for maintenance of the "opaque ON" genotype and phenotype. This work has thus uncovered multiple novel mechanisms that balance pneumococcal epigenetic status and physiology.

In this paper, a novel angular log-periodic folded groove waveguide (ALFGW) slow-wave structure (SWS) has been investigated theoretically and experimentally for application in Ka-band traveling-wave tubes (TWTs). The dispersion relation for the ALFGW is derived analytically, and the dispersion characteristics are calculated for a Ka-band design. The designed SWS is fabricated using oxygen-free-copper that is silver electroplated. The measured cold-test parameters show good agreement with the simulation results, with S21 varying from −2.7 dB to −4.8 dB and S11 better than −13.6 dB over the frequency range of 30–38 GHz. Simulations of beam–wave interactions using a 4850 V and 0.4 A sheet beam with a high aspect ratio of 28:1 indicate an output power of 128 W, corresponding to a maximum gain and electronic efficiency of 18.1 dB and 6.6%, respectively. Due to the log-periodic form, a higher output power, higher efficiency, wider bandwidth, and lower operating voltage are achieved as compared to a TWT based on the conventional folded groove waveguide (FGW) SWS. These results show that the proposed ALFGW SWS has good potential for application in relatively high-power wideband TWTs.

Summary: BRD4 plays a major role in the transcription networks orchestrated by androgen receptor (AR) in castration-resistant prostate cancer (CRPC). Several BET inhibitors (BETi) that displace BRD4 from chromatin are being evaluated in clinical trials for CRPC. Here, we describe mechanisms of acquired resistance to BETi that are amenable to targeted therapies in CRPC. BETi-resistant CRPC cells displayed cross-resistance to a variety of BETi in the absence of gatekeeper mutations, exhibited reduced chromatin-bound BRD4, and were less sensitive to BRD4 degraders/knockdown, suggesting a BRD4-independent transcription program. Transcriptomic analysis revealed reactivation of AR signaling due to CDK9-mediated phosphorylation of AR, resulting in sensitivity to CDK9 inhibitors and enzalutamide. Additionally, increased DNA damage associated with PRC2-mediated transcriptional silencing of DDR genes was observed, leading to PARP inhibitor sensitivity. Collectively, our results identify the therapeutic limitation of BETi as a monotherapy; however, our BETi resistance data suggest unique opportunities for combination therapies in treating CRPC. : Resistance to targeted therapies is a major problem. Pawar et al. investigate the potential mechanisms of acquired resistance to BET inhibitors in prostate cancer and identify actionable targets to overcome the resistance. This study highlights the therapeutic limitation of BET inhibitors as a monotherapy and suggests potential combination therapies in treating prostate cancer. Keywords: prostate cancer, chromatin, BET inhibitors, acquired drug resistance, AR, CDK9, DNA damage, BRCAness, PARP inhibitors

Cullins are central components of the ubiquitin-proteosome system and are activated via a neddylation process mediated by the DCN1–UBC12 complex. Here, the authors develop a small molecule inhibitor of the DCN1–UBC12 interaction that specifically blocks cullin 3 neddylation and can be used to probe the cellular function of cullin 3.

Abstract: Inhibitors of apoptosis proteins (IAPs) regulate apoptosis, but little is known about the role of IAPs in the regulation of immunity. Development of IAP inhibition by second mitochondria-derived activator of caspase (SMAC) mimetics is emerging as a novel therapeutic strategy to treat malignancies. We explored the role of IAPs in allogeneic immunity with 2 distinct yet complementary strategies, namely, chemical and genetic approaches, in clinically relevant models of experimental bone marrow transplantation (BMT). The small-molecule pan-IAP inhibitor SMAC mimetic AT-406 aggravated gastrointestinal graft-versus-host disease (GVHD) in multiple models. The role of specific IAPs in various host and donor cellular compartments was explored by utilizing X-linked IAP (XIAP)– and cellular IAP (cIAP)–deficient animals as donors or recipients. Donor T cells from C57BL/6 cIAP1−/− or XIAP−/− animals demonstrated equivalent GVHD severity and allogeneic responses, both in vivo and in vitro, when compared with B6 wild-type (B6-WT) T cells. By contrast, when used as recipient animals, both XIAP−/− and cIAP1−/− animals demonstrated increased mortality from GVHD when compared with B6-WT animals. BM chimera studies revealed that cIAP and XIAP deficiency in host nonhematopoietic target cells, but not in host hematopoietic-derived cells, is critical for exacerbation of GVHD. Intestinal epithelial cells from IAP-deficient animals showed reduced levels of antiapoptotic proteins as well as autophagy-related protein LC3 after allogeneic BMT. Collectively, our data highlight a novel immune cell–independent but target tissue–intrinsic role for IAPs in the regulation of gastrointestinal damage from GVHD.

A complex permittivity characterization method for liquid samples has been proposed. The measurement is carried out based on a self-designed microwave sensor with a split ring resonator (SRR), the unload resonant frequency of which is 5.05 GHz. The liquid samples in capillary are placed in the resonant zone of the fabricated senor for high sensitivity measurement. The frequency shift of 58.7 MHz is achieved when the capillary is filled with ethanol, corresponding a sensitivity of 97.46 MHz/μL. The complex permittivity of methanol, ethanol, isopropanol (IPA) and deionized water at the resonant frequency are measured and calibrated by the first order Debye model. Then, the complex permittivity of different concentrations of aqueous solutions of these materials are measured by using the calibrated sensor system. The results show that the proposed sensor has high sensitivity and accuracy in measuring the complex permittivity of liquid samples with volumes as small as 0.13 μL. It provides a useful reference for the complex permittivity characterization of small amount of liquid chemical samples. In addition, the characterization of an important biological sample (inositol) is carried out by using the proposed sensor.

PURPOSE: Increased murine double minute 2 (MDM2) expression, independent of p53 status, is associated with increased cancer-specific mortality for men with prostate cancer treated with radiotherapy. We assessed MI-219, a small molecule inhibitor of MDM2 with improved pharmacokinetics over nutlin-3, for sensitization of prostate cancer cells to radiotherapy and androgen deprivation therapy, a standard treatment option for men with high-risk prostate cancer. EXPERIMENTAL DESIGN: The effect of MDM2 inhibition by MI-219 was assessed in vitro and in vivo with mouse xenograft models across multiple prostate cancer cell lines containing varying p53 functional status. RESULTS: MDM2 inhibition by MI-219 resulted in dose- and time-dependent p53 activation and decreased clonogenic cell survival after radiation in a p53-dependent manner. Mechanistically, radiosensitization following inhibition of MDM2 was largely the result of p53-dependent increases in apoptosis and DNA damage as evidenced by Annexin V flow cytometry and γ-H2AX foci immunofluorescence. Similarly, treatment with MI-219 enhanced response to antiandrogen therapy via a p53-dependent increase in apoptotic cell death. Lastly, triple therapy with radiation, androgen deprivation therapy, and MI-219 decreased xenograft tumor growth compared with any single- or double-agent treatment. CONCLUSION: MDM2 inhibition with MI-219 results in p53-dependent sensitization of prostate cancer cells to radiation, antiandrogen therapy, and the combination. These findings support MDM2 small molecule inhibitor therapy as a therapy intensification strategy to improve clinical outcomes in high-risk localized prostate cancer. TRANSLATIONAL RELEVANCE: The combination of radiotherapy and androgen deprivation therapy is a standard treatment option for men with high-risk prostate cancer. Despite improvements in outcomes when androgen deprivation therapy is added to radiation, men with high-risk prostate cancer have significant risk for disease recurrence, progression, and even death within the first 10 years following treatment. We demonstrate that treatment with MI-219 (an inhibitor of MDM2) results in prostate cancer cell sensitization to radiation and androgen deprivation therapy in vitro and in vivo. Triple therapy with MI-219, radiation, and androgen deprivation therapy dramatically decreased tumor growth compared with any single- or double-agent therapy. These findings provide evidence that inhibition of MDM2 is a viable means by which to enhance the efficacy of both radiation and androgen deprivation therapy and thereby improve outcomes in the treatment of prostate cancer. As such, further investigation is warranted to translate these findings to the clinical setting.

Crizotinib is the first anaplastic lymphoma kinase (ALK) inhibitor to have been approved for the treatment of non–small cell lung cancer (NSCLC) harboring an ALK fusion gene, but it has been found that, in the clinic, patients develop resistance to it. Alectinib and ceritinib are second-generation ALK inhibitors which show remarkable clinical responses in both crizotinib-naive and crizotinib-resistant NSCLC patients harboring an ALK fusion gene. Despite their impressive activity, clinical resistance to alectinib and ceritinib has also emerged. In the current study, we elucidated the resistance mechanisms to these second-generation ALK inhibitors in the H3122 NSCLC cell line harboring the EML4-ALK variant 1 fusion in vitro. Prolonged treatment of the parental H3122 cells with alectinib and ceritinib led to two cell lines which are 10 times less sensitive to alectinib and ceritinib than the parental H3122 cell line. Although mutations of ALK in its kinase domain are a common resistance mechanism for crizotinib, we did not detect any ALK mutation in these resistant cell lines. Rather, overexpression of phospho-ALK and alternative receptor tyrosine kinases such as phospho-EGFR, phospho-HER3, and phospho-IGFR-1R was observed in both resistant cell lines. Additionally, NRG1, a ligand for HER3, is upregulated and responsible for resistance by activating the EGFR family pathways through the NRG1-HER3-EGFR axis. Combination treatment with EGFR inhibitors, in particular afatinib, was shown to be effective at overcoming resistance. Our study provides new mechanistic insights into adaptive resistance to second-generation ALK inhibitors and suggests a potential clinical strategy to combat resistance to these second-generation ALK inhibitors in NSCLC.

Enterohemorrhagic Escherichia coli O157:H7 is a major human enteric pathogen capable of causing large outbreaks of severe infections that induce bloody diarrhea, hemorrhagic colitis, and hemolytic uremic syndrome. Its genome contains 177 unique O islands (OIs) including those carrying the main virulence elements, Shiga toxin-converting phages (OI-45 and OI-93) and locus for enterocyte effacement (OI-148). However, many of these islands harbor only genes of unknown function. Here, we demonstrate that OI-29 encodes a newly discovered transcriptional activator, Z0639 (named GmrA), that is required for motility and flagellar synthesis in O157:H7. GmrA directly binds to the promoter of fliA, an RNA polymerase sigma factor, and thereby regulates flagellar genes controlled by FliA. Expression of gmrA is maximal under host conditions (37°C, neutral pH, and physiological osmolarity), and in the presence of host epithelial cells, indicative of a role of this gene in infection by promoting motility. Finally, GmrA was found to be a widespread regulator of bacterial motility and flagellar synthesis in different pathotypes of E. coli. Our work largely enriches our understanding of bacterial motility control, and provides another example of regulators acquired laterally that mediate flagellar synthesis.

To characterize patient-derived xenografts (PDXs) for functional studies, we made whole-genome comparisons with originating breast cancers representative of the major intrinsic subtypes. Structural and copy number aberrations were found to be retained with high fidelity. However, at the single-nucleotide level, variable numbers of PDX-specific somatic events were documented, although they were only rarely functionally significant. Variant allele frequencies were often preserved in the PDXs, demonstrating that clonal representation can be transplantable. Estrogen-receptor-positive PDXs were associated with ESR1 ligand-binding-domain mutations, gene amplification, or an ESR1/YAP1 translocation. These events produced different endocrine-therapy-response phenotypes in human, cell line, and PDX endocrine-response studies. Hence, deeply sequenced PDX models are an important resource for the search for genome-forward treatment options and capture endocrine-drug-resistance etiologies that are not observed in standard cell lines. The originating tumor genome provides a benchmark for assessing genetic drift and clonal representation after transplantation.

Inactivation of the function of tumor suppressor p53 is common in human cancers. In approximately half of human cancers, the tumor suppressor function of p53 is inactivated by deletion or mutation of TP53, the gene encoding p53 protein. In the remaining 50% of human cancers, p53 tumor suppressor function can be effectively inhibited by oncoprotein MDM2 or its homolog MDMX. Since inhibition of p53 by MDM2 or MDMX protein is mediated by their direct interaction with p53, small-molecule inhibitors designed to block the MDM2-p53 or MDMX-p53 protein-protein interaction (MDM2 or MDMX inhibitors) can activate p53 in tumor cells retaining wild-type p53. In the last few years, several classes of potent, selective, and efficacious small molecule MDM2 inhibitors have been designed and developed, and six such compounds are being evaluated in clinical trials as new anticancer drugs. Additionally, non-peptide, small-molecule MDMX inhibitors have been reported. We review herein the design and development of potent small-molecule MDM2 and MDMX inhibitors.

SAR405838 is a potent and specific MDM2 inhibitor currently being evaluated in Phase I clinical trials for the treatment of human cancer. Using the SJSA-1 osteosarcoma cell line which harbors an amplified MDM2 gene and wild-type p53, we have investigated the acquired resistance mechanisms both in vitro and in vivo to SAR405838. Treatment of SJSA-1 cells with SAR405838 in vitro leads to dose-dependent cell growth inhibition, cell cycle arrest and robust apoptosis. However, prolonged treatment of SJSA-1 cells in vitro with SAR405838 results in profound acquired resistance to the drug. Analysis of in vitro-derived resistant cell lines showed that p53 is mutated in the DNA binding domain and can no longer be activated by SAR405838. Treatment of the parental SJSA-1 xenograft tumors with SAR405838 in mice yields rapid tumor regression but the tumors eventually regrow. Culturing the regrown tumors established a number of sublines, which showed only modest (3-5 times) loss of sensitivity to SAR405838 in vitro. Sequencing of the p53 showed that it retains its wild-type status in these in vivo sublines, with the exception of one subline, which harbors a single heterozygous C176F p53 mutation. Using xenograft models of two in vivo derived sublines, which has either wild-type p53 or p53 containing a single heterozygous C176F mutation, we showed that while SAR405838 effectively achieves partial tumor regression in these models, it no longer induces complete tumor regression and tumors resume growth once the treatment is stopped. Harvesting and culturing tumors obtained from a prolonged treatment with SAR405838 in mice established additional in vivo sublines, which all contain a single heterozygous C176F mutation with no additional p53 mutation detected. Interestingly, SAR405838 can still effectively activate p53 in all sublines containing a single heterozygous C176F mutation, with a moderately reduced potency as compared to that in the parental cell line. Consistently, SAR405838 is 3-5 times less effective in all the in vivo derived sublines containing a single heterozygous C176F p53 mutation than in the SJSA-1 parental cell line in assays of cell growth and apoptosis. Computational modeling suggested that a p53 tetramer containing two wild-type p53 molecules and two C176F mutated molecules can maintain the structural stability and interactions with DNA by formation of additional hydrophobic and cation-π interactions which compensate for the loss of sulphur-zinc coordination. Our data thus show that SJSA-1 tumor cells acquire very different levels of resistance in vitro and in vivo to the MDM2 inhibitor SAR405838. Our present study may have a significant implication for the investigation of resistant mechanisms for other classes of anticancer drugs.

Resistance to chemotherapy is a common problem encountered in the treatment of head and neck squamous cell carcinoma (HNSCC). Chemoresistant HNSCC tumors frequently overexpress antiapoptotic proteins, such as BCI-xL. (−)-Gossypol, the negative enantiomer of a cottonseed polyphenol, binds to BCI-xL and was recently been shown to inhibit HNSCC proliferation in vitro. In this study, we assessed the in vivo efficacy of (−)-gossypol in an orthotopic xenograff model of HNSCC, using two human HNSCC cell lines with high BCI-xL expression levels. Both produced tumors in a murine floor-of-mouth model that mimics human HNSCC, exhibiting growth and invasion into adjacent tissues. Mice were randomized into three groups: vehicle control and two daily intraperitoneal (−)-gossypol treatment groups (5 and 15 mg/kg). Tumors were measured twice weekly. In the control group, tumors grew progressively, whereas in (−)-gossypol treatment groups, tumor growth was significantly suppressed. The mitotic rate in tumors from (−)-gossypol-treated animals was significantly lower than that in controls, and an increase in the percentage of apoptotic cells was observed in treated tumors versus controls. Residual tumors remained growth-suppressed for 2 weeks after cessation of (−)-gossypol treatment. Our results demonstrate that (−)-gossypol can inhibit tumor growth in an orthotopic model of aggressive HNSCC.

A kind of coaxial foilless diode is proposed in this paper, with the structure model and operating principle of the diode are given. The current-voltage relation of the coaxial foilless diode and the effects of structure parameters on the relation are studied by simulation. By solving the electron motion equation, the beam deviation characteristic in the presence of external magnetic field in transmission process is analyzed, and the relationship between transverse misalignment with diode parameters is obtained. These results should be of interest to the area of generation and propagation of radial beam for application of generating high power microwaves.

Bcl-2 and Bcl-xL are critical regulators of apoptosis that are overexpressed in a variety of human cancers and pharmacological inhibition of Bcl-2 and Bcl-xL represents a promising strategy for cancer treatment. Using a structure-based design approach, we have designed BM-1197 as a potent and efficacious dual inhibitor of Bcl-2 and Bcl-xL. BM-1197 binds to Bcl-2 and Bcl-xL proteins with Ki values less than 1 nM and shows >1,000-fold selectivity over Mcl-1. Mechanistic studies performed in the Mcl-1 knockout mouse embryonic fibroblast (MEF) cells revealed that BM-1197 potently disassociates the heterodimeric interactions between anti-apoptotic and pro-apoptotic Bcl-2 family proteins, concomitant with conformational changes in Bax protein, loss of mitochondrial membrane potential and subsequent cytochrome c release to the cytosol, leading to activation of the caspase cascade and apoptosis. BM-1197 exerts potent growth-inhibitory activity in 7 of 12 small cell lung cancer cell lines tested and induces mechanism-based apoptotic cell death. When intravenously administered at daily or weekly in H146 and H1963 small-cell lung cancer xenograft models, it achieves complete and long-term tumor regression. Consistent with its targeting of Bcl-xL, BM-1197 causes transit platelet reduction in mice. Collectively, our data indicate that BM-1197 is a promising dual Bcl-2/Bcl-xL inhibitor which warrants further investigation as a new anticancer drug.