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When stimulated, individual lymphocytes program times for division and death that are inherited within families, revealing a common timing mechanism transmitted over generations. Here we describe a threshold-based mechanism for the time to die. By comparing protein levels in control and apoptosis disabled cells, we show that death can be predicted by a cooperating ensemble of BCL-2 family proteins falling below a critical threshold. Single cell measurements predict the time of death with a simple formula, where an additional inhibition factor explains accelerated death induced by BH3 mimetic compounds. Thus, we identify the death timer as a protein-threshold device that underlies signal integration machinery. Together these results reveal that predicting lymphocyte behavior at single cell level, in complex environments, is possible with modular multiscale models that incorporate timers and heritability features of critical proteins.

Tissue homeostasis is maintained by the behaviours of lymphocyte clones responding to antigenic triggers in the face of pathogen, environmental, and developmental challenges. Current methodologies for tracking the behaviour of specific lymphocytes identify clones of a defined antigen-receptor—antigen binding affinity. However, lymphocytes can receive antigenic signals from undefined or endogenous antigens, and the strength of each signal, even for the same lymphocyte, varies with accessory signalling, across tissues and across time. We present a novel fate-mapping mouse, that, by tracking lymphocyte clones and their progenies from induced antigen signals, overcomes these hurdles and provides novel insights into the maintenance of tissue homeostasis. We demonstrate the systems use by investigating the maintenance of localised T cell tolerance in tumour immunity. In a murine tumour model, our system reveals how Tregs differentiate to a reversible, tolerance inducing state within the tumour, and recirculate, while CD8+ T cells failing to recirculate, differentiate to an increasingly exhausted, tolerant state in the tumour. These contrasting T cell behaviours provide means by which immunity can tolerate a particular anatomical niche while maintaining systemic clonal protection. Our system can thus explore lymphocyte behaviours that cannot be tracked by previous methods and will therefore provide novel insights into the fundamental mechanisms underlying immunity’s role in tissue homeostasis.

The transcription factor Myc is critically important in driving cell proliferation, a function that is frequently dysregulated in cancer. To avoid this dysregulation Myc is tightly controlled by numerous layers of regulation. One such layer is the use of distal regulatory enhancers to drive Myc expression. Here, using chromosome conformation capture to examine B cells of the immune system in the first hours after their activation, we reveal a previously unidentified enhancer of myc. The interactivity of this enhancer coincides with a dramatic, but discrete, spike in Myc expression 3 hours post-activation. However, genetic deletion of this region, has little impact on Myc expression, Myc protein level or in vitro and in vivo cell proliferation. Examination of the enhancer deleted regulatory landscape suggests that enhancer redundancy likely sustains Myc expression. This work highlights not only the importance of temporally examining enhancers, but also the complexity and dynamics of the regulation of critical genes such as Myc. Competing Interest Statement The authors have declared no competing interest. Footnotes * New figures have been added because they were not ok in the first submission

Abstract Disclosure: A. Rao: None. B. Ruhle: None. M. Ono: None. J.O. Chinn: None. P. Ruhi-Williams: None. L. Kennedy: None. M.M. Esquivel: None. M.E. Hauser: None. D.E. Azagury: Consultant: Form Health, GI Windows, Endolumik. D. Desai: None. Introduction: While bariatric surgery is the most effective tool for weight loss, the role of glucagon-like peptide 1 receptor agonists (GLP-1) in addition to bariatric surgery is underexplored. This study investigates weight loss outcomes in patients on GLP-1 who receive bariatric surgery, with a focus on the perioperative period. Methods: We conducted a retrospective analysis of all metabolic/bariatric surgical procedures performed at Stanford Health Care between January 1, 2019, and December 31, 2023. Adults with obesity who underwent sleeve gastrectomy or gastric bypass were identified and stratified into treatment groups based on the GLP-1 or GLP-1/glucose-dependent insulinotropic polypeptide (GIP) RA prescribed (semaglutide, liraglutide, dulaglutide, and tirzepatide) and the timing of prescription in relation to their operation. Patients who were on GLP-1 prior to the study period, were prescribed but who did not receive the medication, or were on GLP-1 for <4 months all were excluded. Patients were grouped as follows: Group 1) patients prescribed GLP-1 within 2 years before surgery, but not after; Group 2) patients prescribed GLP-1 within 2 years after surgery, but not before; Group 3) patients prescribed GLP-1 both within 2 years before surgery and 2 years after surgery. Patients not prescribed GLP-1 were included as the control group. The primary outcome was percent total body weight loss. Results: There were 846 patients who received bariatric surgery during the study interval, and 568 met inclusion criteria. There were 424 patients in the control group, 32 patients in Group 1, 66 patients in Group 2, and 46 patients in Group 3. Patients in Group 3 had a significantly higher starting BMI compared to other groups. Patients in Group 2 and Group 3 achieved significantly more total body weight loss than Group 1 and control (30.7% and 32.7%, respectively, vs 28.8% in Group 1, and 27% in the control group, p-value = 0.0002). Discussion: The results underscore the synergistic potential of combining GLP-1 RA with bariatric surgery in achieving greater weight loss in the perioperative period. GLP-1 usage in the perioperative period may prime patients for more effective weight loss, potentially by inducing behavior/physiologic changes that complement the metabolic effect of surgery. Patients with very severe obesity likely benefit the most from starting GLP-1 in the preoperative setting and continuing postoperatively. However, if starting BMI is relatively lower, post-operative GLP-1 alone is effective in augmenting weight loss. Conclusion: Patients on GLP-1 receptor agonists both preoperatively and postoperatively relative to bariatric surgery experienced the greatest weight loss. While existing studies have focused on the use of GLP-1 primarily for weight regain, our findings highlight their potential as adjunctive therapy for weight loss during the critical perioperative period. Presentation: Saturday, July 12, 2025

Head and neck cancers (HNCs) are very common malignancies, and treatment often requires multimodal approaches, including radiotherapy and chemotherapy. Patients with HNC often display a high symptom burden, both due to the disease itself and the adverse effects of the multimodal therapy. Close telemonitoring of symptoms and quality of life during the course of treatment may help to identify those patients requiring early medical support. The App-Controlled Treatment Monitoring and Support for Patients With Head and Neck Cancer (APCOT) trial aimed to investigate the feasibility of integrating electronic patient-reported outcomes (ePROs) in the treatment surveillance pathway of patients with HNC during the course of their radiotherapy. Additionally, the influence of app-based ePRO monitoring on global and disease-specific quality of life and patient satisfaction with treatment was assessed. A total of 100 patients were enrolled in this trial, and 93 patients were evaluable. All patients (100%) in the experimental arm answered ≥80% of the ePRO questions during treatment, reaching the predefined threshold for the feasibility of ePRO monitoring (P<.001 in the binomial test). No clinical or patient-specific factor was found to influence feasibility. Global health and most domains of the general quality of life were comparable between trial arms, but an increased HNC-specific symptom burden was reported by patients undergoing ePRO surveillance. ePRO monitoring resulted in improved patient satisfaction regarding interpersonal manners (P=.01), financial aspects (P=.01), and time spent with a doctor (P=.01). This trial demonstrated the feasibility of incorporating daily app-based ePRO surveillance for patients with HNC undergoing radiotherapy. Our data, for the first time, demonstrate that telemonitoring in this setting led to increased reporting of HNC-specific symptom burden and significantly improved several domains of patient satisfaction. Further analyses are needed to assess whether our findings hold true outside the context of a clinical trial.

Background In recent years, human microbiota, especially gut microbiota, have emerged as an important yet complex trait influencing human metabolism, immunology, and diseases. Many studies are investigating the forces underlying the observed variation, including the human genetic variants that shape human microbiota. Several preliminary genome-wide association studies (GWAS) have been completed, but more are necessary to achieve a fuller picture. Results Here, we announce the MiBioGen consortium initiative, which has assembled 18 population-level cohorts and some 19,000 participants. Its aim is to generate new knowledge for the rapidly developing field of microbiota research. Each cohort has surveyed the gut microbiome via 16S rRNA sequencing and genotyped their participants with full-genome SNP arrays. We have standardized the analytical pipelines for both the microbiota phenotypes and genotypes, and all the data have been processed using identical approaches. Our analysis of microbiome composition shows that we can reduce the potential artifacts introduced by technical differences in generating microbiota data. We are now in the process of benchmarking the association tests and performing meta-analyses of genome-wide associations. All pipeline and summary statistics results will be shared using public data repositories. Conclusion We present the largest consortium to date devoted to microbiota-GWAS. We have adapted our analytical pipelines to suit multi-cohort analyses and expect to gain insight into host-microbiota cross-talk at the genome-wide level. And, as an open consortium, we invite more cohorts to join us (by contacting one of the corresponding authors) and to follow the analytical pipeline we have developed.

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