ZNF683 marks a CD8+ T cell population associated with anti-tumor immunity following anti-PD-1 therapy for Richter syndrome.

Unlike many other hematologic malignancies, Richter syndrome (RS), an aggressive B cell lymphoma originating from indolent chronic lymphocytic leukemia, is responsive to PD-1 blockade. To discover the determinants of response, we analyze single-cell transcriptome data generated from 17 bone marrow samples longitudinally collected from 6 patients with RS. Response is associated with intermediate exhausted CD8 effector/effector memory T cells marked by high expression of the transcription factor ZNF683, determined to be evolving from stem-like memory cells and divergent from terminally exhausted cells. This signature overlaps with that of tumor-infiltrating populations from anti-PD-1 responsive solid tumors. ZNF683 is found to directly target key T cell genes (TCF7, LMO2, CD69) and impact pathways of T cell cytotoxicity and activation. Analysis of pre-treatment peripheral blood from 10 independent patients with RS treated with anti-PD-1, as well as patients with solid tumors treated with anti-PD-1, supports an association of ZNF683high T cells with response.

Junctophilin-2 Regulates Mitochondrial Metabolism.

Right ventricular dysfunction (RVD) is a risk factor for mortality in multiple cardiovascular diseases, but approaches to combat RVD are lacking. Therapies used for left heart failure are largely ineffective in RVD, and thus the identification of molecules that augment RV function could improve outcomes in a wide-array of cardiac limitations. Junctophilin-2 (JPH2) is an essential protein that plays important roles in cardiomyocytes, including calcium handling/maintenance of t-tubule structure and gene transcription. Additionally, JPH2 may regulate mitochondrial function as Jph2 knockout mice exhibit cardiomyocyte mitochondrial swelling and cristae derangements. Moreover, JPH2 knockdown in embryonic stem cell-derived cardiomyocytes induces downregulation of the mitochondrial protein mitofusin-2 (MFN2), which disrupts mitochondrial cristae structure and transmembrane potential. Impaired mitochondrial metabolism drives RVD, and here we evaluated the mitochondrial role of JPH2. We showed JPH2 directly interacts with MFN2, ablation of JPH2 suppresses mitochondrial biogenesis, oxidative capacity, and impairs lipid handling in iPSC-CM. Gene therapy with AAV9-JPH2 corrects RV mitochondrial morphological defects, mitochondrial fatty acid metabolism enzyme regulation, and restores the RV lipidomic signature in the monocrotaline rat model of RVD. Finally, AAV-JPH2 improves RV function without altering PAH severity, showing JPH2 provides an inotropic effect to the dysfunction RV.

Evolutionary history of transformation from chronic lymphocytic leukemia to Richter syndrome.

Richter syndrome (RS) arising from chronic lymphocytic leukemia (CLL) exemplifies an aggressive malignancy that develops from an indolent neoplasm. To decipher the genetics underlying this transformation, we computationally deconvoluted admixtures of CLL and RS cells from 52 patients with RS, evaluating paired CLL-RS whole-exome sequencing data. We discovered RS-specific somatic driver mutations (including IRF2BP2, SRSF1, B2M, DNMT3A and CCND3), recurrent copy-number alterations beyond del(9p21)(CDKN2A/B), whole-genome duplication and chromothripsis, which were confirmed in 45 independent RS cases and in an external set of RS whole genomes. Through unsupervised clustering, clonally related RS was largely distinct from diffuse large B cell lymphoma. We distinguished pathways that were dysregulated in RS versus CLL, and detected clonal evolution of transformation at single-cell resolution, identifying intermediate cell states. Our study defines distinct molecular subtypes of RS and highlights cell-free DNA analysis as a potential tool for early diagnosis and monitoring.

Information Avoidance in Consumer Choice: Do Avoidance Tendencies and Motives Vary by Age?

Prior research suggests that older adults seek less information in consumer choices than younger adults do. However, it remains unclear if intentional information avoidance plays a role in such effects. To test this possibility, we examined age differences in deliberate information avoidance in consumer decisions and explored a range of potential motives. Adult lifespan samples completed two pre-registered online studies, which assessed information avoidance using a slider scale (Study 1, N =195) and a forced-choice task (Study 2, N = 500). In Study 1, age differences in information avoidance were not significant, but methodological limitations could have obscured age effects. In Study 2, age was associated with higher information avoidance. Avoidance was higher among participants who reported that the information would not impact decision preferences, would elicit more negative affect, and would be useless. Although age was associated with lower perceived impact on decision preferences and lower concerns about affective responses, age differences in information avoidance remained significant when these variables were statistically controlled. In conclusion, in the context of consumer choices, deliberate information avoidance is higher among older consumers. Thus, interventions to promote the acquisition of relevant information would benefit from being tailored to the target age group.

Age Differences in Media Consumption and Avoidance With Respect to COVID-19.

BACKGROUND: Older versus younger adults are at greater risk from coronavirus disease 2019 (COVID-19), but descriptive data show they are less likely to seek out related information in the media, although underlying mechanisms remain unclear. METHOD: A representative adult life-span sample (N = 500) completed a preregistered online study assessing changes in media consumption in response to the pandemic, self-reported and behavioral media avoidance, avoidance motives, and demographic, socioemotional, and cognitive covariates. RESULTS: Age was associated with reduced media consumption and higher behavioral media avoidance, but lower self-reported media avoidance and lower endorsement of specific avoidance motives. Age differences in aspects of affect, motivation, and cognition statistically accounted for variations in behavioral avoidance but not for the other age effects. DISCUSSION: Age differences in media use in the context of the COVID-19 pandemic are not explained by deliberate avoidance intentions and motives but associated with broader age variations in socioemotional and cognitive functioning.