Perturbation of calreticulin potentiates CD8+ T cell-mediated antitumor immunity.

Effective immunotherapy relies on the presentation of tumor-derived neoantigens on the major histocompatibility complex class I (MHC-I) to activate CD8+ T cells. Deficiencies in this process are a key mechanism of immune evasion and resistance to checkpoint blockade. In this study, using an in vivo CRISPR-Cas9 screen, we unexpectedly found that inactivation of calreticulin (CALR), and other selected components of the peptide-loading complex (PLC), induced robust CD8+ T cell-mediated immune responses.

A deep learning system for detecting silent brain infarction and predicting stroke risk.

Current brain imaging to detect silent brain infarctions (SBIs) is not feasible for the general population. Here, to overcome this challenge, we developed a retinal image-based deep learning system, DeepRETStroke, to detect SBI and refine stroke risk. We use 895,640 retinal photographs to pretrain the DeepRETStroke system, which encodes a domain-specific foundation model for representing eye-brain connections.

Non-invasive biopsy diagnosis of diabetic kidney disease via deep learning applied to retinal images: a population-based study.

Background: Improving the accessibility of screening diabetic kidney disease (DKD) and differentiating isolated diabetic nephropathy from non-diabetic kidney disease (NDKD) are two major challenges in the field of diabetes care. We aimed to develop and validate an artificial intelligence (AI) deep learning system to detect DKD and isolated diabetic nephropathy from retinal fundus images.

Methods: In this population-based study, we developed a retinal image-based AI-deep learning system, DeepDKD, pretrained using 734 084 retinal fundus images.

Small molecule nitroalkenes inhibit RAD51-mediated homologous recombination and amplify triple-negative breast cancer cell killing by DNA-directed therapies.

Nitro fatty acids (NO -FAs) are endogenously generated lipid signaling mediators from metabolic and inflammatory reactions between conjugated diene fatty acids and nitric oxide or nitrite-derived reactive species. NO -FAs undergo reversible Michael addition with hyperreactive protein cysteine thiolates to induce posttranslational protein modifications that can impact protein function. Herein, we report a novel mechanism of action of natural and non-natural nitroalkenes structurally similar to ( ) 10-nitro-octadec-9-enoic acid (CP-6), recently de-risked by preclinical Investigational New Drug-enabling studies and Phase 1 and Phase 2 clinical trials and found to induce DNA damage in a TNBC xenograft by inhibiting homologous-recombination (HR)-mediated repair of DNA double-strand breaks (DSB).

Small molecule nitroalkenes inhibit RAD51-mediated homologous recombination and amplify triple-negative breast cancer cell killing by DNA-directed therapies.

Nitro fatty acids (NO-FAs) are endogenously generated lipid signaling mediators from metabolic and inflammatory reactions between conjugated diene fatty acids and nitric oxide or nitrite-derived reactive species. NO-FAs undergo reversible Michael addition with hyperreactive protein cysteine thiolates to induce posttranslational protein modifications that can impact protein function. Herein, we report a novel mechanism of action of natural and non-natural nitroalkenes structurally similar to (E) 10-nitro-octadec-9-enoic acid (CP-6), recently de-risked by preclinical Investigational New Drug-enabling studies and Phase 1 and Phase 2 clinical trials and found to induce DNA damage in a TNBC xenograft by inhibiting homologous-recombination (HR)-mediated repair of DNA double-strand breaks (DSB).

Tumor aerobic glycolysis confers immune evasion through modulating sensitivity to T cell-mediated bystander killing via TNF-α.

Metabolic reprogramming toward glycolysis is a hallmark of cancer malignancy. The molecular mechanisms by which the tumor glycolysis pathway promotes immune evasion remain to be elucidated. Here, by performing genome-wide CRISPR screens in murine tumor cells co-cultured with cytotoxic T cells (CTLs), we identified that deficiency of two important glycolysis enzymes, Glut1 (glucose transporter 1) and Gpi1 (glucose-6-phosphate isomerase 1), resulted in enhanced killing of tumor cells by CTLs.