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Abstract Background Chemotherapy remains the standard first-line treatment for pancreatic adenocarcinoma, but with limited efficacy. We aimed to explore the feasibility of adding the PARP inhibitor fuzuloparib to mFOLFIRINOX in the locally advanced/metastatic (LA/M) setting. Methods This was the dose-escalation and -expansion, phase 1b portion of a phase 1b/2 study. Patients were given oral fuzuloparib at escalating doses starting at 30 mg twice daily (BID) plus intravenous mFOLFIRINOX q2w for 8–12 cycles, followed by maintenance fuzuloparib at 150 mg BID. Cohorts at the maximal tolerated dose (MTD) and lower dose of fuzuloparib were expanded. Primary endpoints were dose-limiting toxicity (DLT), MTD, and recommended phase 2 dose (RP2D). Results As of data cutoff on Jan 15, 2023, 39 patients were recruited. 12 patients were enrolled during dose escalation (30 mg [n = 4]; 60 mg [n = 6]; 100 mg [n = 2]). DLT occurred in 1 patient in 60 mg cohort and 1 patient in 100 mg cohort. 60 mg BID was determined to be the MTD, and then 60 and 30 mg cohorts were expanded to 22 and 15 patients, respectively. The most common grade ≥ 3 treatment-related adverse events were hematologic toxicities. Efficacy in 60 mg cohort seemed to be most favorable, with an objective response rate of 50.0% (95% CI, 26.0–74.0) and disease control rate of 94.4% (95% CI, 72.7–99.9). Conclusions First-line fuzuloparib plus mFOLFIRINOX followed by maintenance fuzuloparib was generally safe and showed encouraging anti-tumor activity in patients with LA/M pancreatic adenocarcinoma. The RP2D of fuzuloparib combination was 60 mg BID. Trial registration ClinicalTrials.gov, NCT04228601.

BackgroundOviposition site selection is an important component of vector mosquito reproductive biology. The Asian Tiger mosquito, Aedes albopictus, is a major and important vector of arboviruses including Dengue. Previous studies documented the preference of gravid females for small, dark-colored water containers as oviposition sites, which they sought during the twilight period (dusk) of their locomotor activity. Vision plays an important role in this behavior, and factors such as the shape, size, and color of the container, light intensity, polarization, spectrum, and other visual cues guide the search for suitable oviposition sites, but the mechanistic factors driving this behavior are unclear.Methodology/principal findingsWe blindfolded adult female compound eyes and observed the effects of a lack of vision on the ability to discriminate and utilize preferred oviposition sites. Furthermore, the transcriptomes of blindfolded mosquitoes were screened to identify genes with vision-sensitive expression profiles and gene-editing was used to create non-functional mutations in two of them, rhodopsin-like (mutation designated 'rho-l△807') and kynurenine hydroxylase (mutation designated 'khw'). Behavioral tests of both mutant and control strains revealed that the rho-l△807 mutant mosquitoes had a significant decrease in their ability to search for preferred oviposition sites that correlated with a reduced ability to recognize long-wavelength red light. The khw mutant mosquitoes also had a reduced ability to identify preferred oviposition sites that correlated with reductions in their ability to respond to variations in daily brightness and their ability to discriminate among different color options of the containers and background monochromatic light.Conclusions/significanceThis study underscores the importance of visual cues in the oviposition site selection behavior of adult female Ae. albopictus. We demonstrate that wild-type rho-l and kh gene products play a crucial role in this behavior, as mutants exhibit altered sensitivity or recognition of light intensity and substrate colors.

Optimizing doping profiles has always been a key approach to enhance the performance of silicon modulators. Nevertheless, the pursuit of innovative profiles has encountered barriers in recent times. To tackle this issue, the idea of inverse design, widely adopted in passive photonic devices, can be employed in silicon active devices. As a result, we incorporate the inverse design method with the particle swarm optimization (PSO) algorithm and achieve a G-shaped doping profile for the modulator, exhibiting superior $V_{\pi } L$ of 0.68 V$\cdot$cm and low loss of 9.3 dB/cm. The small-signal frequency response suggests a reliable operation range under reverse biases of 1$\sim$3 V with the bandwidth over 26 GHz. The silicon modulator with a G-shaped design demonstrates remarkable efficiency in modulation and very low loss, suggesting its great potential for application in microwave front-end systems. The use of inverse design shows great potential in enhancing active silicon photonic devices, allowing for faster, higher-capacity, and more reliable data communication systems.

Background Osteoporotic fractures (OFs) are a significant public health issue, which can lead to pain and impaired mobility. The underlying mechanisms of OFs remain unclear, but recent studies have suggested that the circRNA-miRNA-mRNA pathway may play a crucial role. Purpose This study aimed to investigate the potential involvement of the circHIPK3/miR-378a-3p/HDAC4 pathway in the pathogenesis of OFs. Methods We collected tissue and serum samples from 10 patients with OFs and 10 healthy controls. The expression levels of circHIPK3, miR-378a-3p, and HDAC4 were measured by qPCR and WB. Additionally, we quantified the serum levels of bone metabolism-related indicators (ALP, OC, TRAP, OCIF, ODF) using ELISA. Results Our results revealed significant upregulation of circHIPK3 and HDAC4 in both tissue and serum samples from OF patients compared with controls. Simultaneously, we detected a lower expression level of miR-378a-3p in OF tissues and serum than that in the control group. Furthermore, the serum levels of bone metabolism-related indicators ALP, TRAP, OCIF, and ODF were significantly higher in OF patients than in the control group. Interestingly, the serum level of OCIF was lower in OF patients than in the control group. Conclusion Our study provides important evidence for the involvement of the circHIPK3/miR-378a-3p/HDAC4 pathway in the pathogenesis of OFs. The upregulation of circHIPK3 and HDAC4 and downregulation of miR-378a-3p observed in OF patients suggests their potential regulatory effects on bone metabolism. Meanwhile, abnormal expression of serum bone metabolism-related indicators may contribute to the development of OFs by disrupting the balance of bone remodeling.

Due to cost-effectiveness and high efficiency, two-phase case-control sampling has been widely used in epidemiology studies. We develop a semi-parametric empirical likelihood approach to two-phase case-control data under the logistic regression model. We show that the maximum empirical likelihood estimator has an asymptotically normal distribution, and the empirical likelihood ratio follows an asymptotically central chi-square distribution. We find that the maximum empirical likelihood estimator is equal to Breslow and Holubkov (1997)'s maximum likelihood estimator. Even so, the limiting distribution of the likelihood ratio, likelihood-ratio-based interval, and test are all new. Furthermore, we construct new Kolmogorov–Smirnov type goodness-of-fit tests to test the validation of the underlying logistic regression model. Our simulation results and a real application show that the likelihood-ratio-based interval and test have certain merits over the Wald-type counterparts and that the proposed goodness-of-fit test is valid.

Background Claudin18.2 (CLDN18.2) is a tight junction protein that has been identified as a clinically proven target in gastric cancer. Stimulation of 4-1BB with agonistic antibodies is also a promising strategy for immunotherapy and 4-1BB+ T cells were reported to be present within the tumor microenvironment of patients with gastric cancer. However, hepatotoxicity-mediated by 4-1BB activation was observed in clinical trials of agonistic anti-4-1BB monoclonal antibodies.Methods To specifically activate the 4-1BB+ T cells in tumor and avoid the on-target liver toxicity, we developed a novel CLDN18.2×4-1BB bispecific antibody (termed ‘givastomig’ or ‘ABL111’; also known as TJ-CD4B or TJ033721) that was designed to activate 4-1BB signaling in a CLDN18.2 engagement-dependent manner.Results 4-1BB+ T cells were observed to be coexisted with CLDN18.2+ tumor cells in proximity by multiplex immunohistochemical staining of tumor tissues from patients with gastric cancer (n=60). Givastomig/ABL111 could bind to cell lines expressing various levels of CLDN18.2 with a high affinity and induce 4-1BB activation in vitro only in the context of CLDN18.2 binding. The magnitude of T-cell activation by givastomig/ABL111 treatment was closely correlated with the CLDN18.2 expression level of tumor cells from gastric cancer patient-derived xenograft model. Mechanistically, givastomig/ABL111 treatment could upregulate the expression of a panel of pro-inflammatory and interferon-γ-responsive genes in human peripheral blood mononuclear cells when co-cultured with CLDN18.2+ tumor cells. Furthermore, in humanized 4-1BB transgenic mice inoculated with human CLDN18.2-expressing tumor cells, givastomig/ABL111 induced a localized immune activation in tumor as evident by the increased ratio of CD8+/regulatory T cell, leading to the superior antitumor activity and long-lasting memory response against tumor rechallenge. Givastomig/ABL111 was well tolerated, with no systemic immune response and hepatotoxicity in monkeys.Conclusions Givastomig/ABL111 is a novel CLDN18.2×4-1BB bispecific antibody which has the potential to treat patients with gastric cancer with a wide range of CLDN18.2 expression level through the restricted activation of 4-1BB+ T cells in tumor microenvironment to avoid the risk of liver toxicity and systemic immune response.

We experimentally demonstrate a low-loss and low-crosstalk 16-channel 200 GHz-channel-spacing arrayed waveguide grating router (AWGR) with a size of 0.67 × 0.37 mm2, targeting for C-band wavelength division multiplexing (WDM) interconnect routing applications. As a result, the AWGR features a channel spacing of 200±10 GHz, a free spectral range of 25.62 nm and a 3 dB channel bandwidth of 0.9 nm. Based on comprehensive optimal design, the measured characterization revealed 5.55 dB maximum channel loss non-uniformity with 1.13 dB best-case channel insertion loss. Besides, the fabricated device exhibits good cyclic-frequency operation for all 16 × 16 port combinations with channel crosstalk of –15.11 dB.

Wepropose and experimentally demonstrate the ultra-compact mode (de)multiplexers and polarization beam splitter (PBS) based on tapered bent asymmetric directional couplers. The strong coupling strength introduced by tapered bent waveguides significantly shortens the coupling length. As a result, high coupling and conversion efficiencies over a broad bandwidth can be obtained with small footprint. The coupling length of the fabricated PBS and mode (de)multiplexers are less than 4.9 μm and 8.7 μm, respectively. From 1534-1600 nm, the measured insertion loss (IL) is less than 1.4 and 1.55 dB for the TE1-TE0 and TE2-TE0 mode (de)multiplexers, respectively, and the crosstalk (CT) is less than −10 dB. The fabricated PBS shows low insertion loss of 0.55 dB and decent crosstalk of < −14 dB for both polarizations over an 85 nm wavelength range from 1505-1590 nm. Meanwhile, the larger fabrication tolerance ensures that the proposed devices can be readily fabricated with the standard complementary metal-oxide-semiconductor (CMOS) process.

In silicon modulator design, implantation is always a key factor, significantly influencing the doping profile and carrier distribution. As waveguide doping is limited by the compact footprint of the modulator rib, three-dimensional complex optimization is a viable option to improve performance. This work proposes an X-intersected modulator based on two inversely slanted junctions using the effective 3D Monte Carlo method for junction generation. The optimized results show that the modulation efficiency of the design is 1.09 V·cm, while the loss is 18 dB/cm, and the 3 dB bandwidth reaches over 35 GHz owing to the decreased resistance and capacitance of the 3D junction. This work demonstrates the benefits of 3D doping design in silicon modulators, contributing to higher efficiency and avoiding additional PN overlap to introduce lower capacitance. The design of 3D doping profiles well balances the DC and AC performance, and provides novel modulator solutions for high-speed datacom.

An ultra-broadband, compact and CMOS-compatible arbitrary ratio power splitter that is based on a directional coupler is proposed on the silicon-on-insulator (SOI) platform. The proposed device consists of an adiabatic sub-wavelength grating (ASWG) and a conventional directional coupler. The wavelength dependence is greatly reduced by introducing an ASWG in the coupling region of the directional coupler. Simulation results show that our proposed device has an operating bandwidth of 250 nm for arbitrary power splitting ratios, with a transmission power variation of less than 8.5%, covering the wavelength range from 1400 nm to 1650 nm. Meanwhile, the device footprint has been narrowed to less than 46 μm. In addition, the power splitters also exhibit a low excess loss of below 0.24 dB. Our proposed ASWG-assisted power splitters show excellent potential for application in large-scale photonic integrated circuits.

Abstract Background Bi-specific T-cell engager (BiTE) antibody is a class of bispecific antibodies designed for cancer immunotherapy. Blinatumomab is the first approved BiTE to treat acute B cell lymphoblastic leukemia (B-ALL). It brings killer T and target B cells into close proximity, activating patient’s autologous T cells to kill malignant B cells via mechanisms such as cytolytic immune synapse formation and inflammatory cytokine production. However, the activated T-cell subtypes and the target cell-dependent T cell responses induced by blinatumomab, as well as the mechanisms of resistance to blinatumomab therapy are largely unknown. Results In this study, we performed single-cell sequencing analysis to identify transcriptional changes in T cells following blinatumomab-induced T cell activation using single cells from both, a human cell line model and a patient-derived model of blinatumomab-mediated cytotoxicity. In total, the transcriptome of 17,920 single T cells from the cell line model and 2271 single T cells from patient samples were analyzed. We found that CD8+ effector memory T cells, CD4+ central memory T cells, naïve T cells, and regulatory T cells were activated after blinatumomab treatment. Here, blinatumomab-induced transcriptional changes reflected the functional immune activity of the blinatumomab-activated T cells, including the upregulation of pathways such as the immune system, glycolysis, IFNA signaling, gap junctions, and IFNG signaling. Co-stimulatory (TNFRSF4 and TNFRSF18) and co-inhibitory (LAG3) receptors were similarly upregulated in blinatumomab-activated T cells, indicating ligand-dependent T cell functions. Particularly, B-ALL cell expression of TNFSF4, which encodes the ligand of T cell co-stimulatory receptor TNFRSF4, was found positively correlated with the response to blinatumomab treatment. Furthermore, recombinant human TNFSF4 protein enhanced the cytotoxic activity of blinatumomab against B-ALL cells. Conclusion These results reveal a target cell-dependent mechanism of T-cell activation by blinatumomab and suggest that TNFSF4 may be responsible for the resistant mechanism and a potential target for combination therapy with blinatumomab, to treat B-ALL or other B-cell malignancies.

Of the known regulators of atherosclerosis, miRNAs have been demonstrated to play critical roles in lipoprotein homeostasis and plaque formation. Here, we generated a novel animal model of atherosclerosis by knocking in LDLRW483X in C57BL/6 mice, as the W483X mutation in LDLR is considered the most common newly identified pathogenic mutation in Chinese familial hypercholesterolemia (FH) individuals. Using the new in vivo mouse model combined with a well-established atherosclerotic in vitro human cell model, we identified a novel atherosclerosis-related miRNA, miR-23a-3p, by microarray analysis of mouse aortic tissue specimens and human aortic endothelial cells (HAECs). miR-23a-3p was consistently downregulated in both models, which was confirmed by qPCR. Bioinformatics analysis and further validation experiments revealed that the TNFα-induced protein 3 (TNFAIP3) gene was the key target of miR-23a-3p. The miR-23a-3p-related functional pathways were then analyzed in HAECs. Collectively, the present results suggest that miR-23a-3p regulates inflammatory and apoptotic pathways in atherogenesis by targeting TNFAIP3 through the NF-κB and p38/MAPK signaling pathways.

BackgroundDesigning combination drugs for malignant cancers has been restricted due to the scarcity of synergy-medicated targets, while some natural compounds have demonstrated potential to enhance anticancer effects.MethodsWe here explored the feasibility of probing synergy-mediated targets by Berberine (BER) and Evodiamine (EVO) in hepatocellular carcinoma (HCC). Using the genomics-derived HCC signaling networks of compound treatment, NF-κB and c-JUN were inferred as key responding elements with transcriptional activity coinhibited during the synergistic cytotoxicity induction in BEL-7402 cells. Then, selective coinhibitors of NF-κB and c-JUN were tested demonstrating similar synergistic antiproliferation activity.ResultsConsistent with in vivo experiments of zebrafish, coinhibitors were found to significantly reduce tumor growth by 79% and metastasis by 96% compared to blank control, accompanied by anti-angiogenic activity. In an analysis of 365 HCC individuals, the low expression group showed significantly lower malignancies and better prognosis, with the median survival time increased from 67 to 213%, compared to the rest of the groups.ConclusionTogether, NF-κB and c-JUN were identified as promising synergistic inducers in developing anti-HCC therapies. Also, our method may provide a feasible strategy to explore new targeting space from natural compounds, opening opportunities for the rational design of combinational formulations in combatting malignant cancers.

Polarization sensitivity is a severe problem in photonic integration devices and chips based on the high-index contrast Si/SiO2 system. In this paper, a broadband silicon polarization splitter-rotator (PSR) comprised of a bi-level taper and a counter-tapered coupler is proposed with a large fabrication tolerance. The measured insertion loss is lower than 0.7 dB/0.73 dB for the wavelength range from 1470 to 1580 nm with a crosstalk lower than -12.1 dB/-14.7 dB for TE and TM polarization input, respectively. By integrating the PSR with silicon arrayed waveguide gratings and germanium photodetectors (PDs) on a single chip, a polarization-insensitive wavelength-division-multiplexing (WDM) receiver is demonstrated with a polarization-dependent loss as low as 1.21 dB. High-speed operations are also achieved with clear eyes at 10 Gb/s.

The in-plane tailoring of light propagation is significant in on-chip optical interconnections. Recently, an in-plane negative-angle refraction was realized with a thin line of silicon nanoposts, which are at resonance in the first angular momentum channel. This advancement is different from metasurface research, which mostly focuses on out-of-plane operations. In this paper, we experimentally demonstrate that a thin array of doublet silicon nanoposts, in which each unit comprises two tangent nanoposts functioning as an upright interface, remarkably improve efficiency for molding light. The designed upright interface exhibits a broadband response featuring high efficiency in a negative-angle light bending in the wavelength of 1480-1600 nm. The broadband, compactness, low loss, and complementary metal-oxide semiconductor (CMOS) compatibility enable the use of the subwavelength array as an alternative component for on-chip optical control.

By changing the symmetry of a photonic crystal (PC) with a rectangular lattice to straighten one of the isofrequency contours, the PC shows an all-angle quasi-self-collimation (quasi-SC) effect. To investigate the straightness of the isofrequency contour and the quasi-SC effect, we propose a straightness factor L based on the method of least squares. With L ≤ L0 (L0 = 0.01 is the critical value), the isofrequency contour is sufficiently straight to induce the quasi-SC effect with the beam quasi-collimating in the structure. Furthermore, the efficiency of light coupling to the quasi-SC PC is studied and can be greatly improved by applying a carefully designed antireflection structure. This quasi-SC effect of the PC and the coupling structure may see applications in novel optical devices and photonic circuits.

A very novel silicon-on-insulator polarization beam splitter is proposed based on cascaded mode-sorting asymmetric Y-junctions. The width and length of each Y-junction are optimized to achieve correct mode sorting with high conversion efficiency. The numerical simulation results show that the mode conversion efficiency increases with the length of the Y-junction for the waveguide widths varying in a large range. This proposed device has 22 dB polarization extinction ratio in an ultrabroad wavelength range from 1450 to 1750 nm. Fabrication tolerance analysis is also performed with respect to the deviation in device width and height. With such a broad operating bandwidth and robust fabrication tolerance, this device offers potential applications for complementary metal oxide semiconductor (CMOS)-compatible polarization diversity operating across the S, C, L, and U optical communication bands, particularly in the booming 100-Gb/s coherent optical communications based on silicon photonics technology.

We present the design, fabrication, and measurement of a compact and low-loss multimode interference (MMI) coupler based on the silicon nanowire waveguide. The device is carefully designed to achieve both a good performance and a compact size by using the mode matching method. The device is fabricated on silicon-on-insulator (SOI) with 0.13-μm CMOS technology. By measuring the MMI coupler with a cascaded configuration, a very low excess loss of 0.06 dB at the wavelength of 1550 nm is obtained. The device can also work well for a wide wavelength band. The present MMI coupler is very compact with a footprint of ~ 3.6 × 11.5 μm2 for the multimode region.

Berberine has been identified with anti-proliferative effects on various cancer cells. Many researchers have been trying to elucidate the anti-cancer mechanisms of berberine based on differentially expressed genes. However, differentially alternative splicing genes induced by berberine might also contribute to its pharmacological actions and have not been reported yet. Moreover, the potential functional cross-talking between the two sets of genes deserves further exploration. In this study, RNA-seq technology was used to detect the differentially expressed genes and differentially alternative spliced genes in BEL-7402 cancer cells induced by berberine. Functional enrichment analysis indicated that these genes were mainly enriched in the p53 and cell cycle signalling pathway. In addition, it was statistically proven that the two sets of genes were locally co-enriched along chromosomes, closely connected to each other based on protein-protein interaction and functionally similar on Gene Ontology tree. These results suggested that the two sets of genes regulated by berberine might be functionally cross-talked and jointly contribute to its cell cycle arresting effect. It has provided new clues for further researches on the pharmacological mechanisms of berberine as well as the other botanical drugs.

We report the observation of a large-angle self-collimation phenomenon occurring in photonic crystals (PCs) composed of nanorods. Electromagnetic waves incident onto such PCs from directions covering a wide range of incident angles become highly localized along a single array of rods, which results in the narrow-beam propagation without divergence. A propagation length of 0.4 mm is experimentally observed over the wavelength ranging from 1540 nm to 1570 nm even in the large incident angle case, which is a very considerable length scale for on-chip optical interconnection.