Tunable metasurfaces for implementing terahertz controllable NOT logic gate functions.

Compared with traditional electrical logic gates, optical or terahertz (THz) computing logic gates have faster computing speeds and lower power consumption, and can better meet the huge data computing needs. However, there are limitations inherent in existing optical logic gates, such as single input/output channels and susceptibility to interference. Here, we proposed a new approach utilizing polarization-sensitive graphene-vanadium dioxide metasurface THz logic gates. Benefitting from two actively tunable materials, the proposed controlled-NOT logic gate(CNOT LG) enables versatile functionality through a dual-parameter control system. This system allows for the realization of multiple output states under diverse polarized illuminating conditions, aligning with the expected input-output logic relationship of the CNOT LG. Furthermore, to demonstrate the robustness of the designed THz CNOT LG metasurface, we designed an imaging array harnessing the dynamic control capabilities of tunable meta-atoms, facilitating clear near-field imaging. This research is promising for advancing CNOT LG applications in the THz spectrum. It has potential applications in telecommunications, sensing, and imaging.

Real-Time Direction Judgment System for Dual-Frequency Laser Interferometer.

Current real-time direction judgment systems are inaccurate and insensitive, as well as limited by the sampling rate of analog-to-digital converters. To address this problem, we propose a dynamic real-time direction judgment system based on an integral dual-frequency laser interferometer and field-programmable gate array technology. The optoelectronic signals resulting from the introduction of a phase subdivision method based on the amplitude resolution of the laser interferometer when measuring displacement are analyzed. The proposed system integrates the optoelectronic signals to increase the accuracy of its direction judgments and ensures these direction judgments are made in real time by dynamically controlling the integration time. Several experiments were conducted to verify the performance of the proposed system. The results show that, compared with current real-time direction judgment systems, the proposed system makes accurate judgements during low-speed motions and can update directions within 0.125 cycles of the phase difference change at different speeds. Moreover, a sweep frequency experiment confirmed the system's ability to effectively judge dynamic directions. The proposed system is capable of accurate and real-time directional judgment during low-speed movements of a table in motion.

Design and implementation of a real-time compensation algorithm for nonlinear error based on ellipse fitting.

To improve the measurement accuracy of interferometer displacement measurement systems, this study analyzes the characteristics of the interference signal to identify sources of nonlinear errors and develops compensation strategies. Specifically, a model is established for the nonlinear errors of the interferometer, which can be attributed to a laser and polarizing beam splitter (PBS). Following that, the dual orthogonal lock-in amplification algorithm is used to separate and compensate for the frequency uncertainty and amplitude errors. Additionally, a real-time compensation algorithm based on ellipse fitting is proposed to compensate for errors caused by the PBS and the uncertainty of amplitude caused by the light source. Experimental results demonstrate that the peak-to-peak value of the compensated nonlinear error is reduced from 11.62 nm to 5.37 nm.

Regioselective C-H chalcogenylation and halogenation of arenes and alkenes under metal-free conditions.

The reactions of direct Csp2-H chalcogenylation and halogenation of N-arylpyrrolidone under the action of PIFA without a directing group and under metal-free conditions were reported in this paper. Diphenyl selenide/sulfur and selenium phenyl halides were used as reaction reagents to obtain chalcogenylated and halogenated N-arylpyrrolidone products, respectively. The mechanistic studies indicated that a radical pathway was likely involved in these reactions. Preliminary antitumor tests showed that these compounds have moderate to potent activities against human acute leukemia cells K562 in vitro, which may be used as lead compounds for subsequent research.

Separation and compensation of nonlinear errors in sub-nanometer grating interferometers.

In this paper, to separate and compensate the nonlinear error in the grating interferometer, we analyze the source and generation mechanism of this error, deduce the nonlinear error model of the measured signal and the calculated phase signal, and study the characteristics of the established nonlinear error model. The reason why the frequency multiples of ideal phase signals and higher-order nonlinear errors caused by ghost reflections and angular errors of the laser's z-axis are not integers is explained. Then, a nonlinear error separation and compensation method based on cross-correlation coefficient is proposed. Experiments show that the frequency multiplier relationship between the high-order nonlinear error and the ideal interference signal is close to but not equal to 3-fold. The peak-to-peak value of the compensated nonlinear error is reduced from 17.40 nm to 7.05 nm.

Molecular Landscape of ERBB2 Alterations in 14,956 Solid Tumors.

ERBB2 abnormalities frequently occur and serve as rationale therapeutic targets in cancer. In this study, clinical and next-generation sequencing data from 14,956 patients across more than 20 tumor types were collected. A total of 406 (2.7%) patients were identified with ERBB2 amplifications, and 303 (2.0%) patients with pathogenic somatic ERBB2 mutations. ERBB2 amplifications fell most frequently in breast (15.9%) and stomach (8.3%) cancers. Somatic ERBB2 SNVs/indels occurred most common in bladder/urinary tract (7.3%) and intestine (6.1%) cancers. The top mutated ERBB2 SNVs/indels were p.Y772_A775dup (25.5%) and p.S310F/Y (19.9%). Significantly higher rates of ERBB2 SNV/indels were found in women compared to men (2.8% vs. 1.5%, p < 0.0001). CDK12 was the most common co-amplification gene with ERBB2 in cancers with a high frequency of ERBB2 amplifications. Patients with ERBB2 amplifications or mutations had higher TMB compared with patients with non-ERBB2 alterations. The study provided the landscape of ERBB2 alterations across a variety of solid tumors that may benefit from anti-HER2 agents.

Design and Implementation of a Subnanometer Heterodyne Interference Signal Processing Algorithm with a Dynamic Filter.

In this study, a subnanometer heterodyne interference signal processing algorithm with a dynamic filter is proposed. The algorithm can effectively reduce the measurement error caused by the noise introduced in the optical path and circuit. Because of the low signal-to-noise ratio of the measurement signal, a dynamic filter with variable coefficients is designed. The role of the bi-quadrature lock-in amplifier algorithm in the problem of different amplitudes among the measurement signal, reference signal, and uncertainty of the frequency difference of the dual-frequency laser is analyzed. With the aid of the heterodyne interferometry platform, the error in the solution results of the proposed algorithm and the conventional algorithm is compared. The results indicate that the maximum deviation of the phase increment of the algorithm does not exceed 6 mrad, the single-cycle phase difference can be subdivided by 1024, and the system resolution reaches 0.15 nm.

Anti-Swelling, Robust, and Adhesive Extracellular Matrix-Mimicking Hydrogel Used as Intraoral Dressing.

Due to the wet and dynamic environment of the oral cavity, the healing of intraoral wounds, such as tooth extraction wounds, requires stable and firm wound dressings. In clinical practice, cotton balls and gauzes, sponge plugs, or sutures are used to treat extraction wounds, but none of these means can continuously isolate the wound from the intraoral environment and facilitate ideal healing conditions. Herein, inspired by the natural extracellular matrix, a family of wound dressings is developed for intraoral wound repair. Infiltrating a ductile long-chain hydrogel network into a prefabricated, sturdy macromolecular meshwork and in situ crosslinking endowed the composite hydrogel with controllable swelling behaviors and robust mechanical properties. The macromolecular meshwork functioned as the backbone to support the composite and restricts the swelling of the long-chain hydrogel network. In vitro tests verified that this wound dressing can provide durable protection for intraoral wounds against complex irritations. Furthermore, accelerated wound healing occurred when the wound dressing is applied in vivo on a canine tooth extraction model, due to the effective reduction of acute inflammation. These results suggest that this family of bioinspired hydrogels has great potential for application as intraoral wound dressing.

Redefine Hyperprogressive Disease During Treatment With Immune-Checkpoint Inhibitors in Patients With Gastrointestinal Cancer.

OBJECTIVE: Emerging evidence showed that immune checkpoint inhibitors (ICIs) lead to hyperprogressive disease (HPD) in a small proportion of patients. There is no well-recognized standard for the evaluation of HPD. Comprehensive exploration of HPD definition system in gastrointestinal cancer treated with ICI is lacking to date. METHODS: A total of 126 patients with advanced or metastatic gastrointestinal cancer treated with ICI monotherapy were analyzed. Seven definitions of HPD were defined with tumor growth kinetics (TGK) or tumor growth rate (TGR) by including new lesions or not, and with different cutoffs. Incidence and performance of different criteria were compared. Clinicopathologic characteristics and baseline genomic variations associated with HPD were also explored. RESULTS: Tumor growth kinetics ratio of more than two fold that incorporated new lesions into calculation of HPD outperformed other definitions by successfully stratifying 14 patients (11.1%) with both accelerated disease progression (median PFS, 1.62 versus 1.93 months; hazard ratio, 1.85; 95% CI, 0.98 to 3.48; P = 0.059) and worse overall survival (median OS, 3.97 versus 10.23 months; hazard ratio, 2.30; 95% CI, 1.11 to 4.78; P = 0.021). Baseline genomic alterations in circulating tumor DNA, including SMARCA2, MSH6, APC signaling pathway, and Wnt signaling pathway, might be associated with the risk of HPD. CONCLUSION: Incorporating new lesions emerging during the treatment was shown to be reliable for the assessment of TGK. TGK serves as a more convenient way to reflect tumor growth acceleration compared with TGR. Genomic alterations were suggested to be associated with the occurrence of HPD.

Landscape of IDH1/2 mutations in Chinese patients with solid tumors: A pan-cancer analysis.

BACKGROUND: Isocitrate dehydrogenase (IDH) is an enzyme family involved in cell aerobic metabolism of tricarboxylic acid cycle. However, the landscape of IDH mutations in pan-cancer has not been fully characterized. METHODS: Tissue or blood samples were subjected to next-generation sequencing (NGS) for detection the IDH mutation. RESULTS: A total of 28.868 patients from more than 20 solid tumor species were analyzed. A total of 374 cases (1.30%) with IDH mutations were identified. Among all the IDH mutations cases, 80 (21.4%) were biliary tract cancer (BTC), 80 (21.4%) were lung cancer, 57 (15.2%) were liver cancer, and 42 (11.2%) were colorectal cancer. The most common IDH variant were IDH1 and IDH2 which were discovered in 0.81% cases and 0.47% cases, respectively. However, there were significant differences in IDH1 and IDH2 mutation frequency among different tumor species (p = 0.0003). Of the patients with IDH1 mutations, about 53.0% of these mutations occur in codons 132. Codons 172 (25.4%) was high-frequency mutation subtypes in IDH2 mutation. TP53, PBRM1, and BAP1 were the most significantly mutated genes in BTC which were different from others cancer. Moreover, TMB were significantly higher in lung cancer, colorectal cancer, and gastric cancer than BTC (p = 0.0164, p < 0.0001, p = 0.0067, respectively) and BTC patients with IDH mutation had lower TMB compared with wild-type IDH. CONCLUSION: Somatic IDH mutation was found in multiple solid tumors and IDH would be a driver gene in BTC.

The role of TGF-ß pathway alterations in immune regulation as a potential pan-cancer biomarker in immunotherapy.

BACKGROUND: Depending on the context, the transforming growth factor beta (TGF-ß) signaling pathway is involved in opposing cell processes of tumor suppression and tumor promotion. However, the effects of TGF-ß pathway on immunotherapy efficacy have not yet been systematically investigated. METHODS: In this study, we have extracted the available data of whole-exome sequencing, messenger RNA (mRNA) expression, baseline characterization, and prognosis information of 10,912 pan-cancer patients from The Cancer Genome Atlas to explore the role of TGF-ß pathway in immune regulation. Formalin-fixed, paraffin-embedded tissue samples from 6,717 Chinese cancer patients assayed by next-generation sequencing (NGS) were used as a validation cohort (3DMed cohort). Data sets from the public MSK (Memorial Sloan Kettering Cancer Center) cohort (N=1,610) were used to explore the association of TGF-ß pathway with immunotherapy effects. RESULTS: The results showed that TGF-ß pathway alteration was significantly correlated with high microsatellite instability (MSI), high tumor mutational burden, and high neoantigen burden (TNB) (P<0.001 for each). Consistently, the pathway mutations were associated with distinct patterns of immune-related gene expression and tumor-infiltrating immune cells. Patients with TGF-ß pathway mutations exhibited significantly worse prognosis than did the wild-type patients regardless of the interventions [overall survival (OS): hazard ratio (HR) 1.20; 95% confidence interval (CI): 1.08-1.33; P=0.001]. However, when treated with immune checkpoint inhibitors (ICIs), superior survival benefit was observed in patients from the mutation group versus the wild-type group (OS: HR 0.73; 95% CI: 0.61-0.88; P=0.001). CONCLUSIONS: Collectively, our study suggested that mutations in TGF-ß pathway may be associated with positive immune regulation and better efficacy of immunotherapy.

EPHA mutation as a predictor of immunotherapeutic efficacy in lung adenocarcinoma.

BACKGROUND: Ephrin type-A receptors (EPHA) are members of family of receptor tyrosine kinases and are related to tumor immunogenicity and immune microenvironment, however, the association between EPHA mutation (EPHAmut ) and efficacy of immune checkpoint inhibitors (ICIs) has not been investigated in non-small cell lung cancer (NSCLC). METHODS: Multiple cohorts were used to assess the immunotherapeutic predictive performance of EPHAmut , including one discovery cohort (n=79) and two public validation cohort (cohort 1: NSCLC, n=165; cohort 2: pan-cancer, n=1662). The Cancer Genome Atlas cohort was used for prognostic analysis and mechanism exploration. RESULTS: In the discovery cohort, patients with EPHAmut had superior disease control rate (72.2% vs 36.1%, p=0.01) and progression-free survival (PFS) (HR 0.38; 95% CI 0.21 to 0.68; p<0.001) compared with those with wide-type EPHA (EPHAwt ) in NSCLC. The association between EPHAmut and immunotherapy outcomes in NSCLC was consistently observed in the validation cohorts by multivariable models (cohort 1, PFS HR 0.59; 95% CI 0.37 to 0.96; p=0.03; cohort 2, overall survival (OS) HR 0.63; 95% CI 0.41 to 0.98; p=0.04). Further pooled estimates of the discovery and validation cohorts showed that patients with EPHAmut exhibited a significantly longer PFS and OS in lung adenocarcinoma (LUAD) while not squamous cell lung cancer (LUSC). Consistently, mechanism analysis revealed that patients with EPHAmut was associated with increased T cell signatures and downregulated transforming growth factor-ß signaling compared with patients with EPHAwt in LUAD while not LUSC. CONCLUSIONS: Our results demonstrated that EPHAmut is an independent classifier that could stratify patients with LUAD for ICIs therapy. Further prospective studies are warranted. TRIAL REGISTRATION NUMBER: NCC2016JZ-03, NCC2018-092.

Landscape of FGF/FGFR Alterations in 12,372 Chinese Cancer Patients.

Purpose: The aberrant of fibroblast growth factors and their receptors (FGF/FGFR) is an emerging target in the treatment of solid tumors. This study aimed to explore the landscape of FGF/FGFR alterations in a large cohort of cancer patients. Material and Methods: The formalin-fixed paraffin-embedded specimens of cancer patients who have underwent next-generation sequencing (NGS) from 2017 to 2019 in 3DMed Clinical Laboratory Inc. were included in this study. Findings: Of 12,372 Chinese cancer patients with more than 20 tumor types (60% male, median age, 58.0 [IQR, 49.0-66.0]), genomic alterations in FGF, FGFR, and both were observed in 895 (7.2%), 862 (7.0%), and 186 (1.5%) patients, respectively. The highest prevalence of FGF/FGFR mutations fell in esophagus cancer (61.6%, 98/159) and urinary tract cancer (52.7%, 145/275). The most common pathway-level mutations were FGFR single nucleotide variants (635, 5.1%) and FGF amplifications (628, 5.1%). The microsatellite instability status was negatively associated with amplifications (p=0.0017). Conclusion: FGF/FGFR alterations were widely occurred in cancer patients, and the mutational landscape may contribute to the further study design and development of FGF/FGFR inhibitors.

Efficacy and safety of PD-1/PD-L1 inhibitors plus nab-paclitaxel for patients with non-small cell lung cancer who have progressed after platinum-based chemotherapy.

BACKGROUND: Immunotherapy combined with platinum-based chemotherapy is now the standard first-line treatment for non-small cell lung cancer (NSCLC) patients. However, limited evidence exists to show the efficacy of immunotherapy plus taxanes for patients who have progressed after platinum-based chemotherapy. METHODS: The immunotherapy naïve patients with metastatic NSCLC who received anti-PD-1/PD-L1 monotherapy or combined with nab-paclitaxel after prior platinum-based chemotherapy from 2015 to 2018 in PLA General Hospital were identified. The progression-free survival, overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety were assessed. RESULTS: Of 57 patients, 40 were treated with anti-PD-1/PD-L1 monotherapy and 17 were treated with anti-PD-1/PD-L1 plus nab-paclitaxel. With a median OS follow-up of 16.3 months, the nab-paclitaxel group showed significantly longer OS compared with the immune monotherapy group (median, 28.6 months versus 15.9 months, log-rank p = 0.020). When adjusted by covariates in COX proportional regression model, both the treatment group [p = 0.009, hazard ratio (HR) 0.361; 95% confidence interval (CI) 0.168-0.773] and performance status (p = 0.003, HR 0.372; 95% CI 0.192-0.721) demonstrated independent association with the longer OS from combination therapy. In addition, ORR was 23.5% (4/17) in the immune checkpoints inhibitors (ICIs) plus nab-paclitaxel group versus 13.5% (5/37) in immune monotherapy group (p = 0.439), with a DCR of 88.2% (15/17) and 59.5% (22/37) (p = 0.034), respectively. The incidence of grade 3/4 adverse events was 23.5% (4/17) in the combination group and 2.5% (1/40) in the immune monotherapy group. CONCLUSION: PD-1/PD-L1 inhibitor plus nab-paclitaxel resulted in significantly longer OS and higher response versus ICI single agent in metastatic NSCLC patients who have progressed after platinum-based chemotherapy. These findings need to be further explored by prospective studies.

Pathogenic Germline Mutations in Chinese Patients with Gastric Cancer Identified by Next-Generation Sequencing.

BACKGROUND: Gastric cancer (GC) is one of the leading causes of cancer death in China, while the nature of genetic factors related to GC has not been well-studied. OBJECTIVES: To assess the inherited genetic factors regarding pathogenic germline mutations in Chinese GC population. METHODS: Genomic profiling of DNA was performed through next-generation sequencing with 381 cancer-related genes on tissue from patients with GC between January 1, 2017, and May 7, 2019. RESULTS: 470 GC patients were included for analysis. A total of 28 (6.0%) patients were identified to harbor 25 different pathogenic or very likely pathogenic germline mutations in 15 genes. The variants fell most frequently in BRCA2 (n = 6, 1.28%), CHEK2 (n = 5, 1.06%), MUTYH (n = 3, 0.64%), CDH1 (n = 2, 0.43%), and ATM (n = 2, 0.43%). Of all the germline-mutated genes, 66.7% (n = 10) lay in the DNA damage repair pathways. Seven patients were identified to have a high TMB status, among whom two were also identified as MSI-H. Overall, 20 out of the 28 patients (71.4%) carried clinically actionable mutations. CONCLUSIONS: Our study has depicted the spectrum of pathogenic germline mutations in Chinese GC patients, which may provide valuable clues for the assessment of the genetic susceptibility and clinical management in GC.

Identification of Deleterious NOTCH Mutation as Novel Predictor to Efficacious Immunotherapy in NSCLC.

PURPOSE: NOTCH signaling is associated with tumorigenesis, mutagenesis, and immune tolerance in non-small cell lung cancer (NSCLC), indicating its association with the clinical benefit of immune checkpoint inhibitors (ICI). We hypothesized that NOTCH mutation in NSCLC might be a robust predictor of immunotherapeutic efficacy. EXPERIMENTAL DESIGN: Multiple-dimensional data including genomic, transcriptomic, and clinical data from cohorts of NSCLC internal and public cohorts involving immunotherapeutic patients were analyzed. Polymorphism Phenotyping v2 (PolyPhen-2) system was performed to determine deleterious NOTCH mutation (del-NOTCH mut). Further investigation on molecular mechanism was performed in The Cancer Genome Atlas (TCGA) data via CIBERSORT and gene set enrichment analysis. RESULTS: Our 3DMed cohort (n = 58) and other four cohorts (Rizvi, POPLAR/OAK, Van Allen, and MSKCC; n = 1,499) uncovered marked correlation between NOTCH1/2/3 mutation and better ICI outcomes in EGFR/ALK WT population, including objective response rate (2.20-fold, P = 0.001), progression-free survival [HR, 0.61; 95% confidence interval (CI), 0.46-0.81; P = 0.001], and overall survival (HR, 0.56; 95% CI, 0.32-0.96; P = 0.035). Del-NOTCH mut exhibited better predictive function than non-deleterious NOTCH mutation, potentially via greater transcription of genes related to DNA damage response and immune activation. Del-NOTCH mut was not linked with prognosis in TCGA cohorts and chemotherapeutic response, but was independently associated with immunotherapeutic benefit, delineating the predictive, but not prognostic, utility of del-NOTCH mut. CONCLUSIONS: This work distinguishes del-NOTCH mut as a potential predictor to favorable ICI response in NSCLC, highlighting the importance of genomic profiling in immunotherapy. More importantly, our results unravel a possibility of personalized combination immunotherapy as adding NOTCH inhibitor to ICI regimen in NSCLC, for the optimization of ICI treatment in clinical practice.

Association between DNA damage repair gene somatic mutations and immune-related gene expression in ovarian cancer.

BACKGROUND: Defects in DNA damage repair (DDR) system may lead to genomic instability and manifest as increased immunogenicity. DDR deficiency is prevalent in ovarian cancer (OvCa); however, the association of DDR mutation with immune profiles in OvCa remains largely unknown. This knowledge will provide an essential basis to the rational design of biomarker-guided immune combination therapy of OvCa in the future. METHODS: Whole-exome sequencing data of 587 OvCa from The Cancer Genome Atlas (TCGA) were used to determine the expression profiles of 47 immune-related genes and the abundance of tumor-infiltrating immune cells. A Chinese OvCa cohort (n = 220) tested by next-generation sequencing (NGS) was used to validate the association between DDR status and tumor mutation burden (TMB). RESULTS: A total of 19.3% in TCGA cohort and 25.9% in Chinese cohort harbored at least one DDR somatic mutation. DDR deficiency exhibited a distinct immune profile with significant higher expression levels of PTPRCAP, CCL5, IFI16, LAG3, IL15RA, and GBP1 in OvCa in the TCGA cohort. Different DDR pathway deficiency displayed various immune profiles. Increased levels of Th1 cells, TMB, and neoantigen were also observed in DDR-deficient tumors. CONCLUSIONS: DDR deficiency was associated with specific immune signatures in OvCa. Our findings emphasize the urgent need for biomarker-guided rational immune combination therapy to maximize the OvCa patients who could benefit from immunotherapy.