PTPRO-related CD8⁺ T-cell signatures predict prognosis and immunotherapy response in patients with breast cancer

Background: Poor immunogenicity and extensive immunosuppressive T-cell infiltration in the tumor immune microenvironment (TIME) have been identified as potential barriers to immunotherapy success in “immune-cold” breast cancers. Thus, it is crucial to identify biomarkers that can predict immunotherapy efficacy. Protein tyrosine phosphatase receptor type O (PTPRO) regulates multiple kinases and pathways and has been implied to play a regulatory role in immune cell infiltration in various cancers. Methods: ESTIMATE and single-sample gene set enrichment analysis (ssGSEA) were performed to uncover the TIME landscape. The correlation analysis of PTPRO and immune infiltration was performed to characterize the immune features of PTPRO. Univariate and multivariate Cox analyses were applied to determine the prognostic value of various variables and construct the PTPRO-related CD8+ T-cell signatures (PTSs). The Kaplan–Meier curve and the receiver operating characteristic (ROC) curve were used to estimate the performance of PTS in assessing prognosis and immunotherapy response in multiple validation datasets. Results: High PTPRO expression was related to high infiltration levels of CD8+ T cells, as well as macrophages, activated dendritic cells (aDCs), tumor-infiltrating lymphocytes (TILs), and Th1 cells. Given the critical role of CD8+ T cells in the TIME, we focused on the impact of PTPRO expression on CD8+ T-cell infiltration. The prognostic PTS was then constructed using the TCGA training dataset. Further analysis showed that the PTS exhibited favorable prognostic performance in multiple validation datasets. Of note, the PTS could accurately predict the response to immune checkpoint inhibitors (ICIs). Conclusion: PTPRO significantly impacts CD8+ T-cell infiltration in breast cancer, suggesting a potential role of immunomodulation. PTPRO-based PTS provides a new immune cell paradigm for prognosis, which is valuable for immunotherapy decisions in cancer patients

Fumigant emission reductions with TIF warrant regulatory changes

With methyl bromide's phase-out, most growers have turned to alternative fumigants, particularly 1,3-dichloropropene (1,3-D) and chloropicrin. These alternatives are tightly regulated because they are classified as toxic air contaminants and volatile organic compounds; the latter combine with other substances to produce ground-level ozone (smog). Two ambient air monitoring studies were conducted to evaluate the potential of totally impermeable film (TIF) to reduce emissions from shank applications of chloropicrin and 1,3-D. In 2009, a study demonstrated that TIF reduced chloropicrin and 1,3-D peak emissions by 45% and 38%, respectively, but TIF did not reduce total emissions when it was cut after 6 days. In 2011, increasing the tarp period from 5 to 10 days decreased chloropicrin and 1,3-D peak emissions by 88% and 78%, and their total emissions by 64% and 43%, respectively. Concurrent dynamic flux chamber results corroborated the ambient air monitoring data. These studies provide regulatory agencies with mitigation measures that should allow continued fumigant use at efficacious application rates

Preplant 1,3-D treatments test well for perennial crop nurseries, but challenges remain

Preplant fumigation with methyl bromide commonly is used in open-field perennial crop nurseries in California for control of plant-parasitic nematodes, pathogens and weeds. Because this fumigant is being phased out, alternatives are needed to ensure the productivity of the perennial crop nursery industry as well as the ornamental, orchard and vineyard production systems that depend on clean planting stock. As part of the USDA Area-Wide Pest Management Program for Integrated Methyl Bromide Alternatives, several perennial crop nursery projects were conducted in California from 2007 to 2011 to test and demonstrate registered alternative fumigants and application techniques that maximize performance and minimize environmental impacts. The project was designed to evaluate shank application and soil surface sealing methods intended to reduce aboveground emission and improve soil performance of 1,3-dichloropropene, a leading methyl bromide alternative for nurseries. In these garden rose and tree nursery experiments, 1,3-dichloropropene treatments performed well regardless of application techniques. In this article, we highlight recent research and discuss the significance and remaining challenges for adoption of methyl bromide alternatives in this unique nursery stock production system

Expansion of Pathogenic Cardiac Macrophages in Immune Checkpoint Inhibitor Myocarditis.

BACKGROUND: Immune checkpoint inhibitors (ICIs), antibodies targeting PD-1 (programmed cell death protein 1)/PD-L1 (programmed death-ligand 1) or CTLA4 (cytotoxic T-lymphocyte-associated protein 4), have revolutionized cancer management but are associated with devastating immune-related adverse events including myocarditis. The main risk factor for ICI myocarditis is the use of combination PD-1 and CTLA4 inhibition. ICI myocarditis is often fulminant and is pathologically characterized by myocardial infiltration of T lymphocytes and macrophages. Although much has been learned about the role of T-cells in ICI myocarditis, little is understood about the identity, transcriptional diversity, and functions of infiltrating macrophages. METHODS: We used an established murine ICI myocarditis model (Ctla4+/-Pdcd1-/- mice) to explore the cardiac immune landscape using single-cell RNA-sequencing, immunostaining, flow cytometry, in situ RNA hybridization, molecular imaging, and antibody neutralization studies. RESULTS: We observed marked increases in CCR2 (C-C chemokine receptor type 2)+ monocyte-derived macrophages and CD8+ T-cells in this model. The macrophage compartment was heterogeneous and displayed marked enrichment in an inflammatory CCR2+ subpopulation highly expressing Cxcl9 (chemokine [C-X-C motif] ligand 9), Cxcl10 (chemokine [C-X-C motif] ligand 10), Gbp2b (interferon-induced guanylate-binding protein 2b), and Fcgr4 (Fc receptor, IgG, low affinity IV) that originated from CCR2+ monocytes. It is important that a similar macrophage population expressing CXCL9, CXCL10, and CD16α (human homologue of mouse FcgR4) was expanded in patients with ICI myocarditis. In silico prediction of cell-cell communication suggested interactions between T-cells and Cxcl9+Cxcl10+ macrophages via IFN-γ (interferon gamma) and CXCR3 (CXC chemokine receptor 3) signaling pathways. Depleting CD8+ T-cells or macrophages and blockade of IFN-γ signaling blunted the expansion of Cxcl9+Cxcl10+ macrophages in the heart and attenuated myocarditis, suggesting that this interaction was necessary for disease pathogenesis. CONCLUSIONS: These data demonstrate that ICI myocarditis is associated with the expansion of a specific population of IFN-γ-induced inflammatory macrophages and suggest the possibility that IFN-γ blockade may be considered as a treatment option for this devastating condition

Synthesis and Antioxidative Activity of Piperine Derivatives Containing Phenolic Hydroxyl

Piperine was used in this study in its raw form, and different steps, such as amide hydrolysis and amidation, were used to synthesize piperine derivatives containing a phenolic hydroxyl group. DPPH and ABTS free radical scavenging assays were used to assess piperine derivative antioxidant activities. We constructed an AAPH oxidative stress erythrocyte model to study the effect of piperine derivatives on the hemolysis rate of oxidatively damaged erythrocytes as well as the hemoglobin oxidation rate. This AAPH model was also used to determine piperine derivative effects on antioxidant enzyme activity and malondialdehyde (MDA) content. Results showed that spectroscopic methods could synthesize and identify piperine derivatives containing phenolic hydroxyl groups (H-1∼H-3). Moreover, DPPH and ABTS assay results showed that piperine derivative free radical clearance rates were higher compared with the parent compound. Additionally, piperine derivatives (H-1∼H-3) were found to provide protection to AAPH oxidatively damaged erythrocytes in their ability to inhibit AAPH-induced erythrocyte lysis, while hemoglobin oxidation was higher compared with the parent compound. Piperine derivatives may protect intracellular glutathione peroxidase (GSH-Px) antioxidant enzyme system activities, safeguarding against oxidative damage. This study synthesized novel piperine derivatives for use as potential antioxidant agent candidates

Study on horizontal vibration characteristics of high-speed elevator with airflow pressure disturbance and guiding system excitation

This paper aims to study the horizontal vibration dynamic characteristics of high-speed elevator by considering the combined effect of airflow and guiding system. The relationships of lateral force and overturning moment with horizontal displacement, deflection angle displacement and rated speed of the car are mathematically solved, and the horizontal vibration dynamic model of the car under the two excitations is established. For case model, the natural frequency and horizontal vibration response of the car are studied, and the guide-rail excitation frequency and car natural frequency are compared and analyzed. The results indicate that the higher the rated speed is, the more obvious the resonance phenomenon between the guide-rail and car will be in a certain range; the effect of airflow on horizontal vibration acceleration of the car with a speed lower than 6 m/s is small, but when the speed is over 6 m/s, the airflow will greatly affect the single-peak value of horizontal vibration acceleration, which is approximately a quadratic relationship; the deflection angle displacement has an increasing influence on horizontal vibration dynamic response with the increasing speed. The conclusions provide a theoretical guidance for the research and control on the horizontal vibration of high-speed elevator

Intelligent control of horizontal vibration of high-speed elevator based on gas–liquid active guide shoes

Aiming at the inconsistency between the vibration of the car and the car frame in the actual operation of a high-speed elevator and the horizontal vibration caused by the roughness excitation of the guide rail, this study designs a gas–liquid active guide shoe and establishes a horizontal vibration model of the 8-DOF high-speed elevator car system separated from the car and the car frame. Then, the correctness of the model is verified by experiments. Based on this, a fuzzy neural network intelligent vibration reduction controller based on the Mamdani model is designed and simulated by MATLAB. The results show that the root mean square value, mean value, and maximum value of vibration acceleration are reduced by more than 55% after using the fuzzy neural network control method, and the suppression effect is better than that of BP neural network control. Therefore, the intelligent vibration absorption controller designed by this research institute can effectively suppress the horizontal vibration of high-speed elevators

Performance of Nitrogen Fertilization and Nitrification Inhibitors in the Irrigated Wheat Fields

Effective nitrogen (N) management practices are critical to sustain crop production and minimize nitrate (NO3−) leaching loss from irrigated fields in the Columbia Basin (U.S.), but studies on the applied practices are limited. Therefore, from 2014 to 2016, two separate field studies were conducted in sandy loam soils in the region to evaluate the performance of various N fertilizers in spring and winter wheat. The treatments consisted of two nitrification inhibitors (NIs) (Instinct® II and Agrotain® Ultra) in combination with two N fertilizers (urea and urea ammonium nitrate [UAN]) under two application methods (single vs. split-application) and two rates (100% vs. 85% of growers’ standard). The results from these field trials demonstrated that N fertilizer treatments did not affect wheat grain yield (GY) and grain protein (GP). In the spring wheat trial, higher NH4⁺-N content but lower NO3−-N content was observed in the UAN treatments (0–30 cm). However, the application of NIs had no considerable effect on soil N content. In the winter wheat trial, the split N application generally reduced NO3−-N and total mineral nitrogen (TMN) content, especially at 30–60 cm, in comparison to a single application. The use of Instinct® II tended to reduce NO3−-N and TMN contents, while Agrotain® Ultra was not effective in inhibiting nitrification. Our findings suggest that more studies on the effectiveness of NIs and N applications would enable growers to optimize N use efficiency and crop production in the region

Performance of Nitrogen Fertilization and Nitrification Inhibitors in the Irrigated Wheat Fields

Effective nitrogen (N) management practices are critical to sustain crop production and minimize nitrate (NO3−) leaching loss from irrigated fields in the Columbia Basin (U.S.), but studies on the applied practices are limited. Therefore, from 2014 to 2016, two separate field studies were conducted in sandy loam soils in the region to evaluate the performance of various N fertilizers in spring and winter wheat. The treatments consisted of two nitrification inhibitors (NIs) (Instinct® II and Agrotain® Ultra) in combination with two N fertilizers (urea and urea ammonium nitrate [UAN]) under two application methods (single vs. split-application) and two rates (100% vs. 85% of growers’ standard). The results from these field trials demonstrated that N fertilizer treatments did not affect wheat grain yield (GY) and grain protein (GP). In the spring wheat trial, higher NH4⁺-N content but lower NO3−-N content was observed in the UAN treatments (0–30 cm). However, the application of NIs had no considerable effect on soil N content. In the winter wheat trial, the split N application generally reduced NO3−-N and total mineral nitrogen (TMN) content, especially at 30–60 cm, in comparison to a single application. The use of Instinct® II tended to reduce NO3−-N and TMN contents, while Agrotain® Ultra was not effective in inhibiting nitrification. Our findings suggest that more studies on the effectiveness of NIs and N applications would enable growers to optimize N use efficiency and crop production in the region