Notes

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Intestinal ischemia/reperfusion (I/R) injury is a life-threatening complication that leads to inflammation and remote organ damage. The NLRP3 inflammasome regulates the caspase-1-dependent release of IL-1β, an early mediator of inflammation after I/R injury. In this study, we investigated the role of the NLRP3 inflammasome in mice with intestinal I/R injury. Deficiency of NLRP3, ASC, caspase-1/11, or IL-1β prolonged survival after intestinal I/R injury, but neither NLRP3 nor caspase-1/11 deficiency affected intestinal inflammation. Takinib manufacturer Intestinal I/R injury caused acute lung injury (ALI) characterized by inflammation, reactive oxygen species generation, and vascular permeability, which was markedly improved by NLRP3 deficiency. Bone marrow chimeric experiments showed that NLRP3 in non-bone marrow-derived cells was the main contributor to development of intestinal I/R-induced ALI. The NLRP3 inflammasome in lung vascular endothelial cells is thought to be important to lung vascular permeability. Using mass spectrometry, we identified intestinal I/R-derived lipid mediators that enhanced NLRP3 inflammasome activation in lung vascular endothelial cells. Finally, we confirmed that serum levels of these lipid mediators were elevated in patients with intestinal ischemia. To our knowledge, these findings provide new insights into the mechanism underlying intestinal I/R-induced ALI and suggest that endothelial NLRP3 inflammasome-driven IL-1β is a novel potential target for treating and preventing this disorder.There is currently no clinically effective vaccine against cutaneous leishmaniasis because of poor understanding of the Ags that elicit protective CD4+ T cell immunity. In this study, we identified a naturally processed peptide (DLD63-79) that is derived from Leishmania dihydrolipoyl dehydrogenase (DLD) protein. DLD is conserved in all pathogenic Leishmania species, is expressed by both the promastigote and amastigote stages of the parasite, and elicits strong CD4+ T cell responses in mice infected with L. major We generated I-Ab-DLD63-79 tetramer and identified DLD-specific CD4+ T cells at clonal level. Following L. major infection, DLD63-79-specific CD4+ T cells massively expanded and produced effector cytokines (IFN-γ and TNF). This was followed by a gradual contraction, stable maintenance following lesion resolution, and display of memory (recall) response following secondary challenge. Vaccination with rDLD protein induced strong protection in mice against virulent L. major challenge. Identification of Ags that elicit protective immunity and their responding Ag-specific T cells are critical steps necessary for developing effective vaccines and vaccination strategies against infectious agents, including protozoan parasites.The therapeutic use of Abs in cancer, autoimmunity, transplantation, and other fields is among the major biopharmaceutical advances of the 20th century. Broader use of Ab-based drugs is constrained because of their high production costs and frequent side effects. One promising approach to overcome these limitations is the use of highly diluted Abs, which are produced by gradual reduction of an Ab concentration to an extremely low level. This technology was used to create a group of drugs for the treatment of various diseases, depending on the specificity of the used Abs. Highly diluted Abs to IFN-γ (hd-anti-IFN-γ) have been demonstrated to be efficacious against influenza and other respiratory infections in a variety of preclinical and clinical studies. In the current study, we provide evidence for a possible mechanism of action of hd-anti-IFN-γ. Using high-resolution solution nuclear magnetic resonance spectroscopy, we show that the drug induced conformational changes in the IFN-γ molecule. Chemical shift changes occurred in the amino acids located primarily at the dimer interface and at the C-terminal region of IFN-γ. These molecular changes could be crucial for the function of the protein, as evidenced by an observed hd-anti-IFN-γ-induced increase in the specific binding of IFN-γ to its receptor in U937 cells, enhanced induced production of IFN-γ in human PBMC culture, and increased survival of influenza A-infected mice.
Bevacizumab is considered a promising therapy for brain necrosis after radiotherapy, while some patients fail to derive benefit or even worsen. Hence, we developed and validated a radiomics model for predicting the response to bevacizumab in patients with brain necrosis after radiotherapy.

A total of 149 patients (with 194 brain lesions; 101, 51, and 42 in the training, internal, and external validation sets, respectively) receiving bevacizumab were enrolled. In total, 1,301 radiomic features were extracted from the pretreatment MRI images of each lesion. In the training set, a radiomics signature was constructed using the least absolute shrinkage and selection operator algorithm. Multivariable logistic regression analysis was then used to develop a radiomics model incorporated in the radiomics signature and independent clinical predictors. The performance of the model was assessed by its discrimination, calibration, and clinical usefulness with internal and external validation.

The radiomics signature consisted of 18 selected features and showed good discrimination performance. The model, which integrates the radiomics signature, the interval between radiotherapy and diagnosis of brain necrosis, and the interval between diagnosis of brain necrosis and treatment with bevacizumab, showed favorable calibration and discrimination in the training set (AUC 0.916). These findings were confirmed in the validation sets (AUC 0.912 and 0.827, respectively). Decision curve analysis confirmed the clinical utility of the model.

The presented radiomics model, available as an online calculator, can serve as a user-friendly tool for individualized prediction of the response to bevacizumab in patients with brain necrosis after radiotherapy.
The presented radiomics model, available as an online calculator, can serve as a user-friendly tool for individualized prediction of the response to bevacizumab in patients with brain necrosis after radiotherapy.
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