Comprehensive multi-omics analysis of resectable locally advanced gastric cancer: Assessing response to neoadjuvant camrelizumab and chemotherapy in a single-center, open-label, single-arm phase II trial.

BACKGROUND: The current standard of care for locally advanced gastric cancer (GC) involves neoadjuvant chemotherapy followed by radical surgery. Recently, neoadjuvant treatment for this condition has involved the exploration of immunotherapy plus chemotherapy as a potential approach. However, the efficacy remains uncertain. METHODS: A single-arm, phase 2 study was conducted to evaluate the efficacy and tolerability of neoadjuvant camrelizumab combined with mFOLFOX6 and identify potential biomarkers of response through multi-omics analysis in patients with resectable locally advanced GC. The primary endpoint was the pathological complete response (pCR) rate. Secondary endpoints included the R0 rate, near pCR rate, progression-free survival (PFS), disease-free survival (DFS), and overall survival (OS). Multi-omics analysis was assessed by whole-exome sequencing, transcriptome sequencing, and multiplex immunofluorescence (mIF) using biopsies pre- and post-neoadjuvant therapy. RESULTS: This study involved 60 patients, of which 55 underwent gastrectomy. Among these, five (9.1%) attained a pathological complete response (pCR), and 11 (20.0%) reached near pCR. No unexpected treatment-emergent adverse events or perioperative mortality were observed, and the regimen presented a manageable safety profile. Molecular changes identified through multi-omics analysis correlated with treatment response, highlighting associations between HER2-positive and CTNNB1 mutations with treatment sensitivity and a favourable prognosis. This finding was further supported by immune cell infiltration analysis and mIF. Expression data uncovered a risk model with four genes (RALYL, SCGN, CCKBR, NTS) linked to poor response. Additionally, post-treatment infiltration of CD8+ T lymphocytes positively correlates with pathological response. CONCLUSION: The findings suggest the combination of PD-1-inhibitor and mFOLFOX6 showed efficacy and acceptable toxicity for locally advanced GC. Extended follow-up is required to determine the duration of the response. This study lays essential groundwork for developing precise neoadjuvant regimens.

Integration of metabolomics and transcriptomics reveals the therapeutic mechanism underlying Chelidonium majus L. in the treatment of allergic asthma.

BACKGROUND: Chelidonium majus is a well-known traditional Chinese medicine, and has been reported of the effect in relieving cough and asthma. However, the mechanism of action is still unknown. METHODS: Asthmatic SD rats were first sensitized and established through ovalbumin (OVA) motivation. Subsequently, Hematoxylin and eosin (H&E) staining, Masson's trichrome (Masson) staining, Periodic acid-Schiff (PAS) staining and inflammatory cytokines assay of interleukin (IL)-4, IL-6, IL-17 were implemented to evaluate the protective effects of Chelidonium majus on asthma. Then, the effects of Chelidonium majus and their molecular mechanisms of action on asthma were detected based on the integration of transcriptomics and metabolomics analyses. RESULTS: After administration with Chelidonium majus, the histological injuries of inflammation, collagen deposition and mucus secretion in lungs were attenuated and the serum inflammatory cytokines perturbations were also converted. Furthermore, integrated analysis revealed that after Chelidonium majus treatment, 7 different expression genes (DEGs) (Alox15, P4ha1, Pla2g16, Pde3a, Nme1, Entpd8 and Adcy9) and 9 metabolic biomarkers (ADP, Xanthosine, Hypoxanthine, Inosine, prostaglandin E2 (PGE2), prostaglandin F2a (PGF2a), phosphatidylserine, Creatine and LysoPC (10:0)) were discovered to be connected with the enrichment metabolic pathways, including Purine metabolism, Arachidonic acid metabolism, Arginine and proline metabolism and Glycerophospholipid metabolism. The obtained metabolic biomarkers and DEGs were mainly related to energy metabolism and inflammation, and may be potential therapeutic targets. CONCLUSION: Chelidonium majus relieved OVA-induced asthma in rats by regulating the Alox15, P4ha1, Pla2g16, Pde3a, Nme1, Entpd8 and Adcy9 genes expression to restore the disorders in energy metabolism and inflammation.

Low beauvericin concentrations promote PC-12 cell survival under oxidative stress by regulating lipid metabolism and PI3K/AKT/mTOR signaling.

Beauvericin (BEA), a naturally occurring cyclic peptide with good pharmacological activity, has been widely explored in anticancer research. Although BEA is toxic, studies have demonstrated its antioxidant activity. However, to date, the antioxidant mechanisms of BEA remain unclear. Herein, we conducted a comprehensive and detailed study of the antioxidant mechanism of BEA using an untargeted metabolomics approach, subsequently validating the results. BEA concentrations of 0.5 and 1 µM significantly inhibited H2O2-induced oxidative stress (OS), decreased reactive oxygen species levels in PC-12 cells, and restored the mitochondrial membrane potential. Untargeted metabolomics indicated that BEA was primarily involved in lipid-related metabolism, suggesting its role in resisting OS in PC-12 cells by participating in lipid metabolism. BEA combated OS damage by increasing phosphatidylcholine, phosphatidylethanolamine, and sphingolipid levels. In the current study, BEA upregulated proteins related to the PI3K/AKT/mTOR pathway, thereby promoting cell survival. These findings support the antioxidant activity of BEA at low concentrations, warranting further research into its pharmacological effects.

Laser Synthesis of PtMo Single-Atom Alloy Electrode for Ultralow Voltage Hydrogen Generation.

Maximizing atom-utilization efficiency and high current stability are crucial for the platinum (Pt)-based electrocatalysts for hydrogen evolution reaction (HER). Herein, the Pt single-atom anchored molybdenum (Mo) foil (Pt-SA/Mo-L) as a single-atom alloy electrode is synthesized by the laser ablation strategy. The local thermal effect with fast rising-cooling rate of laser can achieve the single-atom distribution of the precious metals (e.g., Pt, Rh, Ir, and Ru) onto the Mo foil. The synthesized self-standing Pt-SA/Mo-L electrode exhibits splendid catalytic activity (31 mV at 10 mA cm-2 ) and high-current-density stability (≈850 mA cm-2 for 50 h) for HER in acidic media. The strong coordination of Pt-Mo bonding in Pt-SA/Mo-L is critical for the efficient and stable HER. In addition, the ultralow electrolytic voltage of 0.598 V to afford the current density of 50 mA cm-2 is realized by utilization of the anodic molybdenum oxidation instead of the oxygen evolution reaction (OER). Here a universal synthetic strategy of single-atom alloys (PtMo, RhMo, IrMo, and RuMo) as self-standing electrodes is provided for ultralow voltage and membrane-free hydrogen production.

A Novel Clustering Method Based on Adjacent Grids Searching.

Clustering is used to analyze the intrinsic structure of a dataset based on the similarity of datapoints. Its widespread use, from image segmentation to object recognition and information retrieval, requires great robustness in the clustering process. In this paper, a novel clustering method based on adjacent grid searching (CAGS) is proposed. The CAGS consists of two steps: a strategy based on adaptive grid-space construction and a clustering strategy based on adjacent grid searching. In the first step, a multidimensional grid space is constructed to provide a quantization structure of the input dataset. The noise and cluster halo are automatically distinguished according to grid density. Moreover, the adaptive grid generating process solves the common problem of grid clustering, in which the number of cells increases sharply with the dimension. In the second step, a two-stage traversal process is conducted to accomplish the cluster recognition. The cluster cores with arbitrary shapes can be found by concealing the halo points. As a result, the number of clusters will be easily identified by CAGS. Therefore, CAGS has the potential to be widely used for clustering datasets with different characteristics. We test the clustering performance of CAGS through six different types of datasets: dataset with noise, large-scale dataset, high-dimensional dataset, dataset with arbitrary shapes, dataset with large differences in density between classes, and dataset with high overlap between classes. Experimental results show that CAGS, which performed best on 10 out of 11 tests, outperforms the state-of-the-art clustering methods in all the above datasets.

Design, Synthesis, and Biological Evaluation of Thioglucoside Analogues of Gliflozin as Potent New Gliflozin Drugs.

In this study, we have investigated the potential of two classes of thioglucoside analogues of gliflozins as antidiabetic drugs, one with substitutions of S-atoms in meta-positions (similar to C-glucoside SGLT2 inhibitors, TAGs A, B, and C) and the other with substitutions of S-atoms in ortho-positions (similar to O-glucoside SGLT2 inhibitors, TAGs D, E, F, and G). These TAGs were confirmed to show good stability against ß-glucosidase and to have no acute toxicity to cultured cells. Most importantly, TAGs D, E, F, and G all showed high inhibitory activity against SGLT2 (IC50: 2.0-5.9 nM) and thus have great potential to be developed as new gliflozin drugs. Compared with the synthesis of C-glucoside gliflozins, the synthesis of TAGs is simple, efficient, and associated with low costs, high yields, and very mild reaction conditions.

A Cross-Sectional Study of Clostridium Difficile Infection in Inpatients with Antibiotic Associated Diarrhea.

BACKGROUND: Clostridium difficile (C. difficile) is a Gram-positive, anaerobic, spore-forming bacillus that can cause pseudomembranous colitis and other C. difficile-associated diseases, resulting in significant morbidity and mortality. The incidence and clinical features vary by geography. METHODS: In this cross-sectional study, we examined the incidence and clinical features of C. difficile infection (CDI) within a 2,900-bed academic medical center in a southern area of China from January 1, 2017, to December 31, 2020. All adult inpatients (aged ≥ 18 years) who submitted loose stool samples for C. difficile testing over this period were considered for the study. RESULTS: This cross-sectional study showed that the average incidence of CDI was 2.07 cases/100,000 hospital patient-days. The mean age of these inpatients was 71.21 ± 2.83 years (range 30 - 93 years), and 83.61% (51/61) were treated in medical units. We found that 85.25% (52/61) of inpatients with CDI were aged > 60 years. Multivariate logistic regression analysis revealed that age > 60 years, and admission to the geriatric treatment unit or neurosurgery treatment unit were indeed independent risk factors for CDI in inpatients. CONCLUSIONS: The incidence of CDI in the southern area of China was low. Age > 60 years, and treatment in geriatric or neurosurgery units were independent risk factors for CDI inpatients.

Efficacy and Safety of Apatinib in Patients with Recurrent or Refractory Melanoma.

BACKGROUND: The prognosis of patients with metastatic malignant melanoma is very poor and partly due to resistance to conventional chemotherapies. The study's objectives were to assess the activity and tolerability of apatinib, an oral small molecule anti-angiogenesis inhibitor, in patients with recurrent advanced melanoma. METHODS: This was a single-arm, single-center phase II trial. The primary endpoint was progression-free survival (PFS) and the secondary endpoints were objective response rate (ORR), disease control rate (DCR), and overall survival (OS). Eligible patients had received at least one first-line therapy for advanced melanoma and experienced recurrence. Apatinib (500 mg) was orally administered daily. RESULTS: Fifteen patients (V660E BRAF status: 2 mutation, 2 unknown, 11 wild type) were included in the analysis. The median PFS was 4.0 months. There were two major objective responses, for a 13.3% response rate. Eleven patients had stable disease, with a DCR of 86.7%. The median OS was 12.0 months. The most common treatment-related adverse events of any grade were hypertension (80.0%), mucositis oral (33.3%), hand-foot skin reaction (26.7%), and liver function abnormalities, hemorrhage, diarrhea (each 20%). The only grade ≥3 treatment-related adverse effects that occurred in 2 patients was hypertension (6.7%) and mucositis (6.7%). No treatment-related deaths occurred. CONCLUSION: Apatinib showed antitumor activity as a second- or above-line therapy in patients with malignant melanoma. The toxicity was manageable. CLINICALTRIALS.GOV IDENTIFIER: NCT03383237.

Generating a new type of polygonal perfect optical vortex.

We generate a new type of perfect optical vortex called the polygonal perfect optical vortex (PPOV) by combining the Bessel-Gauss beam with the high-order cross-phase (HOCP) at the plane of a spatial light modulator (SLM). This is the first time that the HOCP is applied to the Fourier plane of an optical field (POV) instead of directly acting on an optical field itself. Experimentally, the symmetrical PPOV is generated, and the capability of asymmetric distribution is demonstrated. Furthermore, we discuss the influence of parameters on a PPOV. On this basis, we show a novel function of the PPOV that can adjust the energy distribution at the vertices while maintaining the orbital angular momentum as much as possible, which facilitates applications in optical micro-manipulation.

Analysis of misaligned optical rotational Doppler effect by modal decomposition.

The optical rotational Doppler effect (RDE) is closely related to the unique orbital angular momentum (OAM) carried by optical vortex, whose topological charge means the mode of OAM. Compared with the coaxial incidence, the rotational Doppler frequency shift spectrum of a misaligned optical vortex (misaligned RDE) widens according to a certain law. In this paper, an OAM modal decomposition method of the misaligned optical RDE is proposed and the relative intensity of different OAM modes, namely the OAM spectrum, is derived based on an inner product computation. Analyses show that lateral displacements and angular deflections change the distribution of OAM modes relative to the rotation axis of the object. A misaligned Laguerre-Gaussian (LG) vortex can be represented as a specific combination of coaxial LG modes, and the difference between the topological charge of two adjacent modes is 1 or 2 with lateral displacements or angular deflections respectively. An experiment of misaligned optical RDE using a superimposed LG vortex is executed, and the obtained frequency shift spectrum with misaligned incidence expands into a set of discrete signals, which agrees well with the theoretical results. Moreover, we can get the rotation frequency of the object from an expanded frequency spectrum more quickly and accurately based on the difference between two adjacent signal peaks. The proposed method contributes to analyze the misaligned optical RDE comprehensively, which is significant in remote sensing and optical metrology.

A Hybrid Differential Symbiotic Organisms Search Algorithm for UAV Path Planning.

Unmanned aerial vehicle (UAV) path planning is crucial in UAV mission fulfillment, with the aim of finding a satisfactory path within affordable time and moderate computation resources. The problem is challenging due to the complexity of the flight environment, especially in three-dimensional scenarios with obstacles. To solve the problem, a hybrid differential symbiotic organisms search (HDSOS) algorithm is proposed by combining the mutation strategy of differential evolution (DE) with the modified strategies of symbiotic organism search (SOS). The proposed algorithm preserves the local search capability of SOS, and at the same time has impressive global search ability. The concept of traction function is put forward and used to improve the efficiency. Moreover, a perturbation strategy is adopted to further enhance the robustness of the algorithm. Extensive simulation experiments and comparative study in two-dimensional and three-dimensional scenarios show the superiority of the proposed algorithm compared with particle swarm optimization (PSO), DE, and SOS algorithm.

Comparing the diagnostic value of bronchoalveolar lavage fluid galactomannan, serum galactomannanan, and serum 1,3-ß-d-glucan in non-neutropenic respiratory disease patients with invasive pulmonary aspergillosis.

ABSTRACT: The incidence of invasive pulmonary aspergillosis (IPA) is increasing higher in non-neutropenic patients. This study aimed to assess the diagnostic performance of bronchoalveolar lavage fluid (BALF). Galactomannan (GM), serum GM, and 1,3-ß-d-glucan (BDG) in non-neutropenic respiratory disease patients with IPA.A total of 333 non-neutropenic patients suspected IPA were recruited from Xiamen University Zhong Shan hospital between January 2016 and February 2019. One, 33, and 92 cases were diagnosed with proven, and possible IPA.BALF and serum GM were both elevated in the possible IPA group and the probable/proven IPA group (p < 0.001). BALF and serum GM showed a fair correlation in the possible IPA group (r = 0.286, p = 0.008), and moderate correlation in the probable/proven IPA group (r = 0.466, p = 0.005). When the cutoff value was 0.5, the sensitivity and negative likelihood ratio of BALF GM were superior to serum GM (78.3% vs 47.8%, 96.7% vs 91.6%). The specificity and positive likelihood ratio of BALF GM were slightly weaker than serum GM (91.8% vs 95.4%, 56.7% vs 85.0%). When the cutoff value was 1.0, the sensitivity and negative predictive value of BALF GM were better than serum GM (73.9% vs 26.1%, 94.5% vs 88.8%), and the specificity of were equivalent (99.2%). The optimal cutoff value of BALF GM was 0.6, wherein the sensitivity reached 78.3% and the specificity reached 95.4%. Given the extremely low sensitivity of serum BDG at different cutoff values (≥10 µg/mL = 5.3%, ≥20 µg/mL = 2.1%), it cannot be used as a preferred biomarker.The diagnostic performance of BALF GM was superior to other biomarkers and the optimal cutoff value was 0.6.

Rotational Doppler effect detection by LG beams with a nonzero radial index.

The capability to detect the rotational speed of non-cooperative targets in a long distance is a difficult problem to be solved. In recent years, vortex light provides a feasible solution for the measurement of rotational speed for its spiral phase and the orbital angular momentum. Laguerre-Gaussian (LG) mode, as the typical vortex beam, has been widely employed in rotational Doppler effect (RDE) experiments. Here, we show that the nonzero radial index LG beam not only has a specific physical meaning but also can enhance the light intensity and the amplitude of RDE frequency signal relative to a zero radial index LG beam. To this end, we theoretically analyze the reason of intensity enhancement of a nonzero radial index beam and verify the conclusion in a variable control experiment. Our study provides a new aspect of LG beams that can be considered in rotational speed detection based on RDE. It may produce an improvement of the detection range of rotating targets in practical applications.

Direction-sensitive detection of a spinning object using dual-frequency vortex light.

Rotational Doppler effect (RDE) has attracted much attention in recent years which opens new avenues to angular velocity measurement. However, most previous studies used single-frequency vortex light as the detection beam so that the rotational Doppler signal is in the low frequency domain where most of noise signals exist. In this article, we use the dual-frequency 2-fold multiplexed vortex light as the probe beam and transform the Doppler signals from the low frequency domain to the high frequency domain successfully. The results show hardly any noise compared with the measurement in the low frequency domain. More importantly, the direction of rotation can be obtained directly by comparing the modulated signal and the reference signal. Our work demonstrates a new detection method for the RDE and provides a reference for its practical application.

Polygonal shaping and multi-singularity manipulation of optical vortices via high-order cross-phase.

Increasing demand for practical applications is forcing more in-depth research into optical vortices (OVs): from the generation and measurement to the shaping and multi-singularity manipulation of OVs. Herein, we propose a new type of phase structure called the high-order cross-phase (HOCP), which can be employed to modulate OVs to implement polygonal shaping and multi-singularity manipulation simultaneously at far-field. Theoretically, we investigate the propagation characteristics of OVs modulated by a HOCP. In experiments, we achieve the polygonal shaping and multi-singularity manipulation of OVs via HOCPs. On this basis, we discuss the relationship between shapes and the orders of HOCPs, where we find that the order of a HOCP is exactly equal to the number of sides of polygonal OVs. This work provides a novel method to achieve polygonal shaping and multi-singularity manipulation simultaneously, which facilitate applications in optical micro-manipulation and optical communication.

A Novel Simulated Annealing Based Strategy for Balanced UAV Task Assignment and Path Planning.

The unmanned aerial vehicle (UAV) has drawn increasing attention in recent years, especially in executing tasks such as natural disaster rescue and detection, and battlefield cooperative operations. Task assignment and path planning for multiple UAVs in the above scenarios are essential for successful mission execution. But, effectively balancing tasks to better excavate the potential of UAVs remains a challenge, as well as efficiently generating feasible solutions from the current one in constrained explosive solution spaces with the increase in the scale of optimization problems. This paper proposes an efficient approach for task assignment and path planning with the objective of balancing the tasks among UAVs and achieving satisfactory temporal resolutions. To be specific, we add virtual nodes according to the number of UAVs to the original model of the vehicle routing problem (VRP), thus make it easier to form a solution suitable for heuristic algorithms. Besides, the concept of the universal distance matrix is proposed to transform the temporal constraints to spatial constraints and simplify the programming model. Then, a Swap-and-Judge Simulated Annealing (SJSA) algorithm is therefore proposed to improve the efficiency of generating feasible neighboring solutions. Extensive experimental and comparative studies on different scenarios demonstrate the efficiency of the proposed algorithm compared with the exact algorithm and meta-heuristic algorithms. The results also inspire us about the characteristics of a population-based algorithm in solving combinatorial discrete optimization problems.

Detection of spinning objects at oblique light incidence using the optical rotational Doppler effect: erratum.

An erratum is presented to correct funding section of [Opt. Express 27(17), 24781-24792 (2019)].

Generation and measurement of high-order optical vortices by using the cross phase.

We investigate a method for the generation and measurement of high-order optical vortices (OVs) by using the cross phase (CP), which is applied to implement interconversion between Laguerre-Gauss (LG) beams and Hermite-Gaussian beams in the far-field. Experimentally, we generate LG beams, which are a kind of typical OVs, with 20 radial nodes, and measure OVs with topological charges up to 200 via the CP. On this basis, we discuss the relationship between intensity distributions and the waist radius of initial light beams. This work provides an alternative method to generate and measure high-order OVs, which is useful in the fields of optical micro-manipulation, high-dimensional quantum entanglement, and remote sensing of the angular rotation of structured objects.

Detection of spinning objects at oblique light incidence using the optical rotational Doppler effect.

The optical rotational Doppler effect of light beams with angular momentum has recently found applications in the remote sensing of spinning objects. However, most of the reported experimental demonstrations rely on the particular condition of normal incidence, while the general case of oblique incidence has not been addressed yet. Herein, we investigate the optical rotational Doppler effect at oblique incidence based on a local scattering model and formulate the quantitative relation between the Doppler frequency shift and the tilt angle. The analytic results indicate that even if the rotational axis of the spinning object is oriented at a specific tilt angle relative to the light propagation direction, the rotational speed can still be extracted from an asymmetrically broadened Doppler signal. The geometric mean value of the extreme frequency shift is a constant despite the variation of the incident angle. An experiment with obliquely incident and superimposed optical vortices is executed to verify our theoretical predictions, achieving a successful detection of the rotational speed at relatively large tilt angles with a relative error less than 2%. The scheme proposed in this study may be useful for practical applications of rotational Doppler effect in remote sensing and metrology.

Influence of lateral misalignment on the optical rotational Doppler effect.

The discovery of the optical rotational Doppler effect associated with orbital angular momentum of light paves a new way to detect the rotational speed of spinning objects. In this paper, we investigate the influence of lateral misalignment, i.e., the distance between the beam axis of a probe light and the rotation axis of a spinning object, on the rotational Doppler effect. First, we analyze the mechanism of the rotational Doppler effect of optical vortices based on the linear Doppler effect. Specifically, we consider the general case where the center of the optical vortex does not coincide with the rotation axis, and deduce the generalized formula of rotational Doppler shift based on a local scattering model. It is found that the bandwidth of the rotational Doppler signal depends proportionally on the amount of lateral misalignment, whereas the value of rotational Doppler shift remains constant. A proof-of-concept experiment is performed, and the measured results agree well with theoretical predictions. These findings may be useful for practical application of the optical rotational Doppler effect in remote sensing and metrology.