Despite multidisciplinary treatment for patients with advanced gastric cancer, their prognosis remains poor. Therefore, the development of novel therapeutic strategies is urgently needed, and ...immunotherapy utilizing anti‐programmed death 1/‐programmed death ligand‐1 mAb is an attractive approach. However, as there is limited information on how programmed death ligand‐1 is upregulated on tumor cells within the tumor microenvironment, we examined the mechanism of programmed death ligand‐1 regulation with a particular focus on interferon gamma in an in vitro setting and in clinical samples. Our in vitro findings showed that interferon gamma upregulated programmed death ligand‐1 expression on solid tumor cells through the JAK‐signal transducer and activator of transcription pathway, and impaired the cytotoxicity of tumor antigen‐specific CTL against tumor cells. Following treatment of cells with anti‐programmed death ligand‐1 mAb after interferon gamma‐pre‐treatment, the reduced anti‐tumor CTL activity by interferon gamma reached a higher level than the non‐treatment control targets. In contrast, programmed death ligand‐1 expression on tumor cells also significantly correlated with epithelial‐mesenchymal transition phenotype in a panel of solid tumor cells. In clinical gastric cancer samples, tumor membrane programmed death ligand‐1 expression significantly positively correlated with the presence of CD8‐positive T cells in the stroma and interferon gamma expression in the tumor. The results suggest that gastric cancer patients with high CD8‐positive T‐cell infiltration may be more responsive to anti‐programmed death 1/‐programmed death ligand‐1 mAb therapy.
PD‐L1 levels significantly correlated with CD8 (stroma) levels (P = .018), but not with CD3 nor CD4 in tumor/stroma in gastric cancer. Furthermore, PD‐L1 levels also significantly positively correlated with tumor IFN‐γ levels. The results suggests that upregulation of PD‐L1 may result from increased IFN‐γ production by CTLs which migrate to the tumor during immune activation.
The World Health Organization has declared SARS-CoV-2 virus outbreak a worldwide pandemic. However, there is very limited understanding on the immune responses, especially adaptive immune responses ...to SARS-CoV-2 infection. Here, we collected blood from COVID-19 patients who have recently become virus-free, and therefore were discharged, and detected SARS-CoV-2-specific humoral and cellular immunity in eight newly discharged patients. Follow-up analysis on another cohort of six patients 2 weeks post discharge also revealed high titers of immunoglobulin G (IgG) antibodies. In all 14 patients tested, 13 displayed serum-neutralizing activities in a pseudotype entry assay. Notably, there was a strong correlation between neutralization antibody titers and the numbers of virus-specific T cells. Our work provides a basis for further analysis of protective immunity to SARS-CoV-2, and understanding the pathogenesis of COVID-19, especially in the severe cases. It also has implications in developing an effective vaccine to SARS-CoV-2 infection.
•SARS-CoV-2-specific antibodies are detected in COVID-19 convalescent subjects•Most COVID-19 convalescent individuals have detectable neutralizing antibodies•Cellular immune responses to SARS-CoV-2 are found in COVID-19 convalescent subjects•Neutralization antibody titers correlate with the numbers of virus-specific T cells.
In blood samples from COVID-19 convalescent subjects, Ni et al. have detected SARS-CoV-2-specific humoral and cellular immunity. Most subjects display serum neutralizing activities, which correlate with the numbers of virus-specific T cells.
In this paper, we systematically investigate the nonlocal Hirota equation with nonzero boundary conditions via Riemann–Hilbert method and multi-layer physics-informed neural networks algorithm. ...Starting from the Lax pair of nonzero nonlocal Hirota equation, we first give out the Jost function, scattering matrix, their symmetry and asymptotic behavior. Then, the Riemann–Hilbert problem with nonzero boundary conditions are constructed and the precise formulae of N-double poles solutions and N-simple poles solutions are written by determinants. Different from the local Hirota equation, the symmetry of scattering data for nonlocal Hirota equation is completely different, which results in disparate discrete spectral distribution. In particular, it could be more complicated and difficult to obtain the symmetry of scattering data under the circumstance of double poles. Besides, we also analyze the asymptotic state of one-double poles solution as t→∞. Whereafter, the multi-layer physics-informed neural networks algorithm is applied to research the data-driven soliton solutions of the nonzero nonlocal Hirota equation by using the training data obtained from the Riemann–Hilbert method. Most strikingly, the integrable nonlocal equation is firstly solved via multi-layer physics-informed neural networks algorithm. As we all know, the nonlocal equations contain the PT symmetry P:x→−x, or T:t→−t, which are different with local ones. Adding the nonlocal term into the neural network, we can successfully solve the integrable nonlocal Hirota equation by multi-layer physics-informed neural networks algorithm. The numerical results show that the algorithm can recover the data-driven soliton solutions of the integrable nonlocal equation well. Noteworthily, the inverse problems of the integrable nonlocal equation are discussed for the first time through applying the physics-informed neural networks algorithm to discover the parameters of the equation in terms of its soliton solution.
•We study the nonlocal Hirota equation with NZBCs, which is more complicated than one with ZBCs.•We give a more complex case of double poles for the nonlocal Hirota equation under ZBCs.•We study this nonlocal system with the PINN method for the first time.
The worldwide prevalence of infections caused by antibiotic-resistant Gram-negative bacteria poses a serious threat to public health due to the limited therapeutic alternatives. Cationic peptides ...represent a large family of antibiotics and have attracted interest due to their diverse chemical structures and potential for combating drug-resistant Gram-negative pathogens. Here, we analyze 7395 bacterial genomes to investigate their capacity for biosynthesis of cationic nonribosomal peptides with activity against Gram-negative bacteria. Applying this approach, we identify two novel compounds (brevicidine and laterocidine) showing bactericidal activities against antibiotic-resistant Gram-negative pathogens, such as Pseudomonas aeruginosa and colistin-resistant Escherichia coli, and an apparently low risk of resistance. The two peptides show efficacy against E. coli in a mouse thigh infection model. These findings may contribute to the discovery and development of Gram-negative antibiotics.
We consider the exact rogue periodic wave (rogue wave on the periodic background) and periodic wave solutions for the Chen–Lee–Liu equation via the odd-th order Darboux transformation. Then, the ...multi-layer physics-informed neural networks (PINNs) deep learning method is applied to research the data-driven rogue periodic wave, breather wave, soliton wave and periodic wave solutions of well-known Chen–Lee–Liu equation. Especially, the data-driven rogue periodic wave is learned for the first time to solve the partial differential equation. In addition, using image simulation, the relevant dynamical behaviors and error analysis for there solutions are presented. The numerical results indicate that the rogue periodic wave, breather wave, soliton wave and periodic wave solutions for Chen–Lee–Liu equation can be generated well by PINNs deep learning method.
•The rogue periodic wave and periodic wave for CLL equation are derived firstly.•The PINN method is applied to research the data-driven solutions of CLL equation.•The data-driven rogue periodic wave is learned for the first time to solve the PDE.
Background
Immunotherapy targeting PD-1 provides a limited survival benefit in patients with unresectable advanced or recurrent gastric cancer (GC). Beside PD-L1, the expression of inhibitory ligands ...such as CEACAM-1 and LSECtin on GC cells account for this limitation. Here we assessed their expression and immune suppressive effect in GC patients.
Methods
Using multiplexed immunohistochemistry staining, we evaluated the distribution of different inhibitory ligands, including PD-L1, CEACAM-1, LSECtin, and MHC class II, in 365 GC patients. We analyzed their correlations and overall survival (OS) based on the expression of each inhibitory ligand and the independent prognostic factors that affect OS. Subsequently, we evaluated the additive effect of anti-PD-1 mAb or anti-PD-L1 mAb with/without anti-Lag-3 mAb with/without anti-Tim-3 mAb in cytotoxic assay using tumor-antigen specific CTL clones against GC cell lines.
Results
Co-expression of the inhibitory ligands for PD-1, Tim-3, and Lag-3 was observed in the largest proportion (34.7%). CEACAM-1, LSECtin, and MHC class II expression showed significant correlation with PD-L1 expression and OS. Multivariable analysis demonstrated that CEACAM-1 low is an independent prognostic factor. Furthermore, combining dual and triple ICIs yielded additive effect on cytotoxicity of CTL clones against each immune inhibitory ligand positive GC cell lines.
Conclusions
Our findings suggested that the expression of inhibitory ligands for Tim-3 and Lag-3 on GC cells serve as potential biomarkers to predict the response to anti-PD-1 therapy and the combinatorial immunotherapy with ICIs targeting for PD-1, Tim-3, and Lag-3 has a therapeutic potential for GC patients.
Gastric cancer heterogeneity represents a barrier to disease management. We generated a comprehensive single-cell atlas of gastric cancer (>200,000 cells) comprising 48 samples from 31 patients ...across clinical stages and histologic subtypes. We identified 34 distinct cell-lineage states including novel rare cell populations. Many lineage states exhibited distinct cancer-associated expression profiles, individually contributing to a combined tumor-wide molecular collage. We observed increased plasma cell proportions in diffuse-type tumors associated with epithelial-resident KLF2 and stage-wise accrual of cancer-associated fibroblast subpopulations marked by high INHBA and FAP coexpression. Single-cell comparisons between patient-derived organoids (PDO) and primary tumors highlighted inter- and intralineage similarities and differences, demarcating molecular boundaries of PDOs as experimental models. We complemented these findings by spatial transcriptomics, orthogonal validation in independent bulk RNA-sequencing cohorts, and functional demonstration using in vitro and in vivo models. Our results provide a high-resolution molecular resource of intra- and interpatient lineage states across distinct gastric cancer subtypes.
We profiled gastric malignancies at single-cell resolution and identified increased plasma cell proportions as a novel feature of diffuse-type tumors. We also uncovered distinct cancer-associated fibroblast subtypes with INHBA-FAP-high cell populations as predictors of poor clinical prognosis. Our findings highlight potential origins of deregulated cell states in the gastric tumor ecosystem. This article is highlighted in the In This Issue feature, p. 587.
Oocyte quality, which is directly related to reprogramming competence, is a major important limiting factor in animal cloning efficiency. Compared with oocytes matured in vivo, in vitro matured ...oocytes exhibit lower oocyte quality and reprogramming competence primarily because of their higher levels of reactive oxygen species. In this study, we investigate whether supplementing the oocyte maturation medium with melatonin, a free radical scavenger, could improve oocyte quality and reprogramming competence. We found that 10−9 M melatonin effectively alleviated oxidative stress, markedly decreased early apoptosis levels, recovered the integrity of mitochondria, ameliorated the spindle assembly and chromosome alignment in oocytes, and significantly promoted subsequent cloned embryo development in vitro. We also analyzed the effects of melatonin on epigenetic modifications in bovine oocytes. Melatonin increased the global H3K9 acetylation levels, reduced the H3K9 methylation levels, and minimally affected DNA methylation and hydroxymethylation. Genome‐wide expression analysis of genes in melatonin‐treated and nontreated oocytes was also conducted by high‐throughput RNA sequencing. Our results indicated that melatonin ameliorates oocyte oxidative stress and improves subsequent in vitro development of bovine cloned embryos.
Melatonin supplementation during in vitro maturation of oocyte effectively alleviated oxidative stress, markedly decreased early apoptosis levels, recovered the integrity of mitochondria, ameliorated the spindle assembly and chromosome alignment in oocytes, and significantly promoted subsequent development of cloned embryo.
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