Most follicular lymphomas (FLs) demonstrate an indolent clinical course with favorable outcomes; however, a fraction of patients experiences progression of disease within 24 months (POD24) and has adverse outcomes. This study aimed to determine the predictive risk factors for POD24 in patients with FL, and the characteristics of the microenvironment in FL with POD24. By multivariate analysis, we revealed that increased Ki-67 expression was associated with POD24 events in patients with FL (hazard ratio [HR]: 6.29, 95% confidence interval [CI]: 1.96–20.22, p = 0.0020). Additionally, patients with FL with POD24 demonstrated immune cell reduction by immunohistochemistry analysis. Our results help better understand the therapeutic strategies for FL with POD24.

Obesity imprints an epigenetic memory in adipose tissue macrophages (ATMs), allowing proinflammatory traits to persist after weight loss. However, mechanisms by which ATMs sustain efferocytosis and influence adipose tissue mass remain unclear. Here, we demonstrate that aberrant messenger RNA splicing, caused by dysfunction of the CWC22/exon junction complex, limits efferocytosis in macrophages during postobesity weight loss. Multiomics and gene-targeting approaches revealed that 51.9% of the obesity-induced differentially spliced genes in ATMs remained altered after weight loss, identifying persistent splicing alterations as a prominent component of obesity memory, with one-quarter of these changes dependent on CWC22. Scarb1 exon skipping increased scavenger receptor class B type II (SR-BII) expression, promoting the formation of SR-BI/SR-BII heterodimers that were subsequently targeted for endoplasmic reticulum–associated degradation. This reduced surface SR-BI in macrophages, suppressed efferocytosis and inosine release from dead cells, and impaired inosine-induced lipolysis in white adipose tissue. Restoring Scarb1 splicing with an antisense oligonucleotide rescued SR-BI expression, efferocytosis, inosine availability, and fat loss in Cwc22 -deficient mice. Immunohistochemical analysis of human adipose tissue specimens revealed predominant nuclear localization of CWC22 in ATMs from lean individuals, whereas this nuclear localization was markedly diminished in ATMs from obese individuals. These findings reveal that aberrant alternative splicing in macrophages underlies resistance to postobesity weight loss and suggest that splicing-targeted therapies may counteract obesity memory.

Background: Boron neutron capture therapy (BNCT) is a type of targeted radiotherapy with considerable therapeutic potential that may be combined with immune checkpoint inhibitors (ICIs) to enhance systemic antitumor immunity. Its efficacy relies on the efficient and safe delivery of boron to cancer cells. This study evaluated the acute toxicity of a self-assembling peptide-based boron carrier composed of A6K and sodium borocaptate (BSH) at a 1:10 molar ratio (A6K/BSH boron drug), which had previously shown excellent tumor-selective accumulation and prolonged intracellular retention. Methods: A single-dose intraperitoneal toxicity study was performed in 6-week-old BALB/c mice (n = 6 per group; 3 males and 3 females). Animals received BSH-equivalent doses of 0, 30, 100, 300, or 600 mg/kg and were observed for 14 days. Mortality, clinical signs, body weight, gross necropsy findings, and histopathological characteristics of major organs were then assessed. Results: No mortality or treatment-related clinical signs were observed. Body weight changes were comparable between the control and treated groups. Gross necropsy revealed no treatment-related abnormalities. Histopathology showed mild hepatocellular hypertrophy and granular degeneration without dose dependency. No other organ toxicities or sex-related differences were detected. Conclusions: A single intraperitoneal administration of the A6K/BSH boron drug up to 600 mg/kg (BSH-equivalent) produced no evident acute systemic toxicity, suggesting that the approximate lethal dose exceeds 600 mg/kg for both sexes. This initial safety assessment supports the further development of the A6K/BSH boron drug as a boron delivery agent for BNCT. Further studies are needed to confirm its safety under clinically relevant conditions.