Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is a life-threatening hyperinflammatory syndrome triggered by EBV infection. It often becomes relapsed or refractory (r/r), given that etoposide-based regimens cannot effectively clear the virus. r/r EBV-HLH is invariably lethal in adults without allogeneic hematopoietic stem cell transplantation. Here, we performed a retrospective analysis of 7 r/r EBV-HLH patients who were treated with nivolumab on a compassionate-use basis at West China Hospital. All 7 patients tolerated the treatment and 6 responded to it. Five of them achieved and remained in clinical complete remission with a median follow-up of 16 months (range, 11.4-18.9 months). Importantly, both plasma and cellular EBV-DNAs were completely eradicated in 4 patients. Single-cell RNA-sequencing analysis showed that HLH syndrome was associated with hyperactive monocytes/macrophages and ineffective CD8 T cells with a defective activation program. Nivolumab treatment expanded programmed death protein-1–positive T cells and restored the expression of HLH-associated degranulation and costimulatory genes in CD8 T cells. Our data suggest that nivolumab, as a monotherapy, provides a potential cure for r/r EBV-HLH, most likely by restoring a defective anti-EBV response.

Red blood cells (RBCs) are the most abundant cells in the body, possessing unique biological and physical properties. RBCs have demonstrated outstanding potential as delivery vehicles due to their low immunogenicity, long-circulating cycle, and immune characteristics, exhibiting delivery abilities. There have been several developments in understanding the delivery system of RBCs and their derivatives, and they have been applied in various aspects of biomedicine. This article compared the various physiological and physical characteristics of RBCs, analyzed their potential advantages in delivery systems, and summarized their existing practices in biomedicine. Graphical Abstract

Prognostic value of diametrically polarized tumor-associated macrophages in multiple myeloma Prognostic value of diametrically polarized tumor-associated macrophages in multiple myeloma

Summary: The tomato ripening process contains complex changes, including ethylene signalling, cell wall softening and numerous metabolic changes. So far, much is still unknown about how tomato plants precisely coordinate fruit maturation and metabolic regulation. In this paper, the ERF family transcription factor SlERF.G3‐Like in tomato was found to be involved in the regulation of ethylene synthesis, cell wall degradation and the flavonoid pathway. We show that the master ripening regulator SlRIN was found to directly bind to the promoter region of SlERF.G3‐Like to activate its expression. In addition, we managed to increase the production of resveratrol derivatives from ~1.44 mg/g DW in E8:VvStSy line to ~2.43 mg/g DW by crossing p35S: SlERF.G3‐Like with the E8:VvStSy line. Our data provide direct evidence that SlERF.G3‐Like, a hierarchical transcriptional factor, can directly manipulate pathways in which tomatoes can coordinate fruit maturation and metabolic changes. We also attest that SlERF.G3‐Like can be used as an effective tool for phenylpropanoid metabolic engineering.

Background: Doxycycline was demonstrated in a retrospective study to be associated with greater survival in patients with light chain amyloidosis. Therefore, we prospectively compared the efficacy of bortezomib-cyclophosphamide-dexamethasone (CyBorD) and CyBorD combined with doxycycline for cardiac light chain amyloidosis. Methods: This was a multicenter, open-label, randomized controlled trial. Patients with Mayo 2004 stage II to III light chain amyloidosis were included. Patients were randomized to doxycycline 100 mg twice daily along with 9 cycles of CyBorD (doxycycline group) or to 9 cycles of CyBorD alone (control group). The primary outcome was 2-year progression-free survival (PFS). PFS was defined as the time from randomization to death, hematologic progression, or organ progression (heart, kidney or liver). Hematologic progression was defined on the basis of a substantial increase in free light chain. An increase in either NT-proBNP (N-terminal pro B-type natriuretic peptide) or cardiac troponin was the main criterion for defining cardiac progression. Cardiac PFS, defined as the time from randomization to cardiac progression or death, was compared between groups in an exploratory analysis. The corresponding treatment hazard ratio was estimated with a Cox regression model. Results: One hundred forty patients underwent randomization, with 70 in each group. The median age was 61 years (range, 33–78 years) with a male:female ratio of 1.75:1. Stage II disease was present in 34 (48.6%) and 33 (47.1%) patients in the doxycycline and control groups, respectively. After a median follow-up duration of 24.4 months, 32 of 70 (45.7%) patients in the doxycycline group and 30 of 70 (42.9%) patients in the control group experienced progression. PFS was not significantly different between groups (hazard ratio, 0.97 [95% CI, 0.59–1.60]; P =0.91). Cardiac progression occurred in 29 of 70 (41.4%) patients in the doxycycline group and 26 of 70 (37.1%) patients in the control group. The death rates for both groups by the end of follow-up was the same, 25 of 70 (35.7%). No significant differences were observed for either cardiac PFS (hazard ratio, 0.91 [95% CI, 0.54–1.55]; P =0.74) or overall survival (hazard ratio, 1.04 [95% CI, 0.60–1.81]; P =0.89). Conclusions: Our trial demonstrated that doxycycline combined with CyBorD failed to prolong PFS or cardiac PFS compared with CyBorD alone in cardiac light chain amyloidosis. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03401372.

The tumor suppressor p53 is inactivated by over hundreds of heterogenous mutations in cancer. Here, we purposefully selected phenotypically reversible temperature-sensitive (TS) p53 mutations for pharmacological rescue with thermostability as the compound-screening readout. This rational screening identified antiparasitic drug potassium antimony tartrate (PAT) as an agent that can thermostabilize the representative TS mutant p53-V272M via noncovalent binding. PAT met the three basic criteria for a targeted drug: availability of a co-crystal structure, compatible structure-activity relationship, and intracellular target specificity, consequently exhibiting antitumor activity in a xenograft mouse model. At the antimony dose in clinical antiparasitic therapy, PAT effectively and specifically rescued p53-V272M in patient-derived primary leukemia cells in single-cell RNA sequencing. Further scanning of 815 frequent p53-missense mutations identified 65 potential PAT-treatable mutations, most of which were temperature sensitive. These results lay the groundwork for repurposing noncovalent antiparasitic antimonials for precisely treating cancers with the 65 p53 mutations.