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The activation of CD40-mediated signaling in antigen-presenting cells is a promising therapeutic strategy to promote immune responses against tumors. Most agonistic anti-CD40 antibodies currently in development require the Fcγ-receptor (FcγR)-mediated crosslinking of CD40 molecules for a meaningful activation of CD40 signaling but have limitations due to dose-limiting toxicities. Here we describe the identification of CD40 antibodies which strongly stimulate antigen-presenting cells in an entirely FcγR-independent manner. These Fc-silenced anti-CD40 antibodies induce an efficient upregulation of costimulatory receptors and cytokine release by dendritic cells. Finally, the most active identified anti-CD40 antibody shows activity in humanized mice. More importantly, there are no signs of obvious toxicities. These studies thus demonstrate the potent activation of antigen-presenting cells with anti-CD40 antibodies lacking FcγR-binding activity and open the possibility for an efficacious and safe combination therapy for cancer patients. [ABSTRACT FROM AUTHOR]

We propose and experimentally demonstrate digitally programmable optical frequency combs (OFCs), featured by binary phase distribution and flat power envelope among comb lines for the first time. In the proposed simple generation scheme, a programmable optimized binary sequence is generated and applied to phase modulate a CW lightwave, creating an OFC with joint manipulation of both binary phase distribution and flat power envelope. Moreover, by digitally programing of the binary sequence, the generated OFC shows high tunability on comb spacing and comb-line number. In the experiments, tunable comb spacing of 20, 10, 5, 2 MHz and tunable comb-line number of 21, 51, 101 are demonstrated, while retaining excellent binary phase and flat power envelope. Such an agile joint manipulation of both phase and power paves a new way for promising phase-correlated applications of OFCs, such as the covert communications and weak signal detection. [ABSTRACT FROM AUTHOR]

Gastric carcinoma is the third major cause of cancer‐related death in China. Bcl‐2 and other BH3 family proteins are critically important in the process of apoptosis pathway, which may be a promising target. APG‐1252‐M1 specifically connects to Bcl‐2 and Bcl‐xl. The antitumor effect of APG‐1252‐M1 in six gastric cancer cells was identified by the Cell Counting Kit‐8 assay. The expression level of proapoptotic proteins was evaluated by Western blot. Meanwhile, the cell cycle and apoptosis distributions were analyzed by flow cytometry and JC‐1. Xenograft models were used to investigate the roles of APG‐1252‐M1 in suppressing the growth of tumors and enhancing the chemotherapy antitumor effect. The antitumor effect of APG‐1252‐M1 was time‐ and dose‐dependent and acted by initiating apoptosis. The change of cell cycle distribution was not discovered in gastric cancer cells treated with APG‐1252‐M1. APG‐1252‐M1 also exhibited synergy with chemotherapy in vivo. The combined group inhibited xenograft tumor growth more obviously than the other groups. Moreover, Ki‐67 was remarkably decreased in the combination group compared to other groups. In conclusion, APG‐1252‐M1 had a strong antitumor effect by inducing apoptosis and was synergistic with chemotherapy. [ABSTRACT FROM AUTHOR]

Despite therapeutic advances, the effective treatment for relapsed or refractory diffuse large B-cell lymphoma (DLBCL) remains a major clinical challenge. Evasion of apoptosis through upregulating antiapoptotic B-cell lymphoma-2 (BCL-2) family members and p53 inactivation, and abnormal activation of B-cell receptor signaling pathway are two important pathogenic factors for DLBCL. In this study, our aim is to explore a rational combination of BCL-2 inhibitor plus Brutons tyrosine kinase (BTK) blockade or p53 activation for treating DLBCL with the above characteristics. We demonstrated that a novel BCL-2 selective inhibitor APG-2575 effectively suppressed DLBCL with BCL-2 high expression via activating the mitochondrial apoptosis pathway. BTK inhibitor ibrutinib combined with BCL-2 inhibitors showed synergistic antitumor effect in DLBCL with mean expression of BCL-2 and myeloid cell leukemia-1 (MCL-1) through upregulating the expression level of BIM and modulating MCL-1 and p-Akt expression. For p53 wild-type DLBCL with high expression of BCL-2, APG-2575 showed strong synergic effect with mouse double minute 2 (MDM2)p53 inhibitor APG-115 that can achieve potent antitumor effect and markedly prolong survival in animal models. Collectively, our data provide an effective and precise therapeutic strategy through rational combination of BCL-2 and BTK or MDM2p53 inhibitors for DLBCL, which deserves further clinical investigation. [ABSTRACT FROM AUTHOR]

Measurement on intra-pulse parameters of complex microwave signals within a wide frequency coverage is essential for radar and communication systems. In this paper, a photonic approach based on a dual-port Mach–Zehnder interferometer (MZI) configuration is proposed to measure the intra-pulse parameters of phase/frequency-coded microwave signals. In the proposed approach, a light wave is externally modulated by a complex signal to be measured under the carrier suppression mode, and then sent to the dual-port MZI to perform frequency-to-power mapping. The optical powers at the two outputs of the MZI are detected as two instantaneous amplitudes, such that an amplitude comparison function (ACF) directly associated with the instantaneous frequency is derived via a division between the two instantaneous amplitudes. Multiple intra-pulse parameters are then identified through temporal analysis of the instantaneous amplitude, ACF, and instantaneous frequency. Measurements to pulsed microwave signals with intra-pulse modulation formats, including phase-shift keying, frequency-shift keying, and linear frequency modulation, are described theoretically and demonstrated experimentally. In addition, the performance of the proposed approach in terms of the signal-to-noise ratio and the minimum power level is discussed. [ABSTRACT FROM AUTHOR]

Highlights from the article: In article number 1800240, Xihua Zou, Zizheng Cao, Wei Pan, Jianping Yao, Antonius M. J. Koonen, and co-workers develop a versatile and powerful integrated circuit of microwave photonics, which enables seven fundamental functions across microwave signal generation, transmission, and processing. Particularly, this photonic circuit is demonstrated for direct deployment in real-world applications, e.g., high-speed railways and broadband wireless communications, accelerating fundamental research from the laboratory to daily life.

Microwave photonics (MWP) studies the interaction between microwaves and optical waves for the generation, transmission, and processing of microwave signals (i.e., three key domains), taking advantage of the broad bandwidth and low loss offered by modern photonics. Integrated MWP using photonic integrated circuits (PICs) can reach a compact, reliable, and green implementation. Most PICs, however, are recently developed to perform one or more functions restricted inside a single domain. Herein, as highly desired, a multifunctional PIC is proposed to cover the three key domains. The PIC is fabricated on an InP platform by monolithically integrating four laser diodes and two modulators. Using the multifunctional PIC, seven fundamental functions across microwave signal generation, transmission, and processing are demonstrated experimentally. Outdoor field trials for electromagnetic environment surveillance along in‐service high‐speed railways are also performed. The success of such a PIC marks a key step forward for practical and massive MWP implementations. [ABSTRACT FROM AUTHOR]

An optical frequency comb (OFC)-assisted covert wireless communication system with multiple access and enhanced capacity is proposed and experimentally demonstrated. In the scheme, signals in multiple channels are spread and mixed together to use a single transmitter and then received by individual receivers according to multiple access channels. The mixed signal is highly contaminated by noise to achieve high concealment in both the time and frequency domains, and then effectively recovered as different channels using the OFC assisted analog deep denoising technique. In experiments, mixed signals of 16 access channels with a signal-to-noise ratio (SNR) from -18 to -5 dB are accommodated, showing high covertness and 16× capacity enhancement (16×10 Mbit/s). Mutual interference among different channels is also analyzed and greatly eliminated by phases optimization in the spectral-spreading process. This scheme can greatly improve the time and spectrum utilization efficiency, which will be of great significance for enabling multiple access, large capacity, and high security for wireless communications.

We propose a fully digital programmable optical frequency comb (OFC) generation scheme based on binary phase-sampling modulation, wherein an optimized bit sequence is applied to phase modulate a narrow-linewidth light wave. Programming the bit sequence enables us to tune both the comb spacing and comb-line number (i.e., number of comb lines). The programmable OFCs are also characterized by ultra-flat spectral envelope, uniform temporal envelope, and stable bias-free setup. Target OFCs are digitally programmed to have 19, 39, 61, 81, 101, or 201 comb lines and to have a 100, 50, 20, 10, 5, or 1 MHz comb spacing. As a demonstration, a scanning-free temperature sensing system using a proposed OFC with 1001 comb lines was also implemented with a sensitivity of 0.89°C/MHz.

Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Despite improved remission rates, current treatment regimens for AML are often associated with a very poor prognosis and adverse effects, necessitating more effective and safer agents. B-cell leukemia/lymphoma 2 (Bcl-2) family proteins regulate apoptotic pathway that can be targeted with small molecule inhibitors. APG-1252-12A is a Bcl-2 homology (BH)-3 mimetic that specifically binds to Bcl-2 and Bcl-xl, which has shown efficacy in some Bcl-2 dependent hematological cancers. In this study, we investigated whether APG-1252-12A inhibits the growth of five leukemia cell lines in a concentration- or time-dependent manner by MTS assay. Following treatment of AML cell line HL-60 with this compound, cell apoptosis was detected using flow cytometry and nuclear condensation was observed after Hoechst 33258 dye. Immunoblotting for cytochrome c, cleaved caspase-3 and PARP-1 cleavage was used to demonstrate the mechanism of inducing mitochondria-dependent apoptosis by APG-1252-12A. Our findings showed that this new compound inhibited cell proliferation in five leukemia cell lines and induced apoptotic death. There was a link between the level of Bcl-2 protein and IC50. APG-1252-12A targeted mitochondria and induced caspase-dependent apoptosis by inducing the HL-60 cell cytochrome c released, PARP cleavage and caspase activation. These data suggested that APG-1252-12A is a candidate drug for the in vivo analysis and clinical evaluation in AML.

Dedifferentiated papillary thyroid cancer (DePTC) is characterized by aggressive growth, recurrence, distant metastasis, and resistance to radioactive iodine (RAI) therapy. DePTC is also accompanied by poor prognosis and high early-mortality. Nevertheless, most DePTC cells show intact p53 downstream functionality. In cells with wild-type p53, the murine double minute2 (MDM2) protein interacts with p53 and abrogates its activity. Inhibition of the MDM2-p53 interaction restores p53 activity and leads to cell cycle arrest and apoptosis. Restoring p53 function by inhibiting its interaction with p53 suppressors such as MDM2 is thus a promising therapeutic strategy for the treatment of DePTC. The novel MDM2-p53 interaction antagonist APG115 is an analogue of SAR405838, and is being tested in a phase I clinical trial. In this study, we evaluated the efficacy of APG115 as a single-agent to treat DePTC. APG115 diminished the viability of p53 wild-type DePTC cells and induced cell cycle arrest and apoptosis. In a human xenograft mouse model, APG115 elicited robust tumor regression and cell apoptosis. These data demonstrate that further research is warranted to determine whether APG115 can be used to effectively treat DePTC patients.

A photonic approach for both wideband Doppler frequency shift (DFS) measurement and direction ambiguity resolution is proposed and experimentally demonstrated. In the proposed approach, a light wave from a laser diode is split into two paths. In one path, the DFS information is converted into an optical sideband close to the optical carrier by using two cascaded electro-optic modulators, while in the other path, the optical carrier is up-shifted by a specific value (e.g., from several MHz to hundreds of MHz) using an optical-frequency shift module. Then the optical signals from the two paths are combined and detected by a low-speed photodetector (PD), generating a low-frequency electronic signal. Through a subtraction between the specific optical frequency shift and the measured frequency of the low-frequency signal, the value of DFS is estimated from the derived absolute value, and the direction ambiguity is resolved from the derived sign (i.e., + or -). In the proof-of-concept experiments, DFSs from -90 to 90 kHz are successfully estimated for microwave signals at 10, 15, and 20 GHz, where the estimation errors are lower than ±60  Hz. The estimation errors can be further reduced via the use of a more stable optical frequency shift module.