Citations

TPS8124 Background: Immune checkpoint inhibitor (ICI)–based regimens are standard first-line therapy for metastatic non–small-cell lung cancer (NSCLC) without actionable driver mutations; however, most patients experience disease progression within 12 months. A subset develop oligoprogression, defined by progression at a limited number of metastatic sites with otherwise controlled disease. Oligoprogression represents a therapeutic window in which local ablative therapy could be used to prolong disease control. In the prior phase II CURB trial, SBRT was shown to significantly prolong progression-free survival (PFS) in patients with oligoprogressive NSCLC. Methods: CCTG-BR38 is an international, multicenter, open-label, randomized phase III trial conducted through the NCI National Clinical Trials Network. Adults with stage IV NSCLC receiving first-line ICI ± chemotherapy who develop ≤5 extracranial oligoprogressive lesions are randomized 1:1 to: (1) switch to second-line standard systemic therapy or (2) SBRT (30 Gy in 3 fractions) to all oligoprogressive sites followed by continuation of the same first-line systemic therapy. Randomization is stratified by type of first-line systemic therapy (ICI alone vs ICI + chemotherapy), number of oligoprogressive lesions (1–2 vs 3–5), and ECOG performance status (0-1 vs 2). Patients with treated, stable brain metastases are eligible. Primary Endpoints: Dual primary endpoints are PFS and overall survival (OS). Secondary endpoints include safety (CTCAE v5.0), patient-reported adverse events (PRO-CTCAE), quality of life (EORTC QLQ-C30/LC13), and cost-effectiveness (EQ-5D-5L; Canadian sites). Optional blood and tissue collection for exploratory biomarker analyses are planned. Statistical Considerations: A total of 320 patients (160 per arm) will be enrolled. The sample size is based on detecting a HR of 0.7 for OS (an improvement in median OS from 10 to 14.3 months) with 80% power using a 1-sided 2% level test (the overall 1-sided 2.5% type I error will be assigned 2% to OS and 0.5% to PFS). Interim analyses for futility and efficacy are planned. Current Status: The trial was centrally activated on April 3, 2025. Accrual is ongoing across Canadian and US NCTN sites. Clinical trial information: NCT06686771 .

We present optimized settings for ramp times and ion mobility range in trapped ion mobility spectrometry experiments involving single cell analysis.

AbstractBackgroundBipolar disorder (BD) is characterized by episodes of depression and mania and disrupted circadian rhythms. Lithium is an effective therapy for BD, but only 30%–40% of patients are fully responsive. Preclinical models show that lithium alters circadian rhythms. However, it is unknown if the circadian rhythm effects of lithium are essential to its therapeutic properties.MethodsIn secondary analyses of a multi‐center, prospective, trial of lithium for BD, we examined the relationship between circadian rhythms and therapeutic response to lithium. Using standardized instruments, we measured morningness, diurnal changes in mood, sleep, and energy (circadian rhythm disturbances) in a cross‐sectional study of 386 BD subjects with varying lithium exposure histories. Next, we tracked symptoms of depression and mania prospectively over 12 weeks in a subset of 88 BD patients initiating treatment with lithium. Total, circadian, and affective mood symptoms were scored separately and analyzed.ResultsSubjects with no prior lithium exposure had the most circadian disruption, while patients stable on lithium monotherapy had the least. Patients who were stable on lithium with another drug or unstable on lithium showed intermediate levels of disruption. Treatment with lithium for 12 weeks yielded significant reductions in total and affective depression symptoms. Lithium responders (Li‐Rs) showed improvement in circadian symptoms of depression, but non‐responders did not. There was no difference between Li‐Rs and nonresponders in affective, circadian, or total symptoms of mania.ConclusionsExposure to lithium is associated with reduced circadian disruption. Lithium response at 12 weeks was selectively associated with the reduction of circadian depressive symptoms. We conclude that stabilization of circadian rhythms may be an important feature of lithium's therapeutic effects. Clinical Trials Registry: NCT0127253.

Senescent cells exacerbate COVID-19 Cellular senescence is a state elicited in response to stress signals and is associated with a damaging secretory phenotype. The number of senescent cells increases with advanced age and this in turn drives age-related diseases. Camell et al. show that senescent cells have an amplified inflammatory response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (see the Perspective by Cox and Lord). This response is communicated to nonsenescent cells, suppressing viral defense mechanisms and increasing the expression of viral entry proteins. In old mice infected with a SARS-CoV-2–related virus, treatment with senolytics to reduce the senolytic cell burden reduced mortality and increased antiviral antibodies. Science , abe4832, this issue p. eabe4832 ; see also abi4474, p. 281

AbstractBackgroundLithium is regarded as a first‐line treatment for bipolar disorder (BD), but partial response and non‐response commonly occurs. There exists a need to identify lithium non‐responders prior to initiating treatment. The Pharmacogenomics of Bipolar Disorder (PGBD) Study was designed to identify predictors of lithium response.MethodsThe PGBD Study was an eleven site prospective trial of lithium treatment in bipolar I disorder. Subjects were stabilized on lithium monotherapy over 4 months and gradually discontinued from all other psychotropic medications. After ensuring a sustained clinical remission (defined by a score of ≤3 on the CGI for 4 weeks) had been achieved, subjects were followed for up to 2 years to monitor clinical response. Cox proportional hazard models were used to examine the relationship between clinical measures and time until failure to remit or relapse.ResultsA total of 345 individuals were enrolled into the study and included in the analysis. Of these, 101 subjects failed to remit or relapsed, 88 achieved remission and continued to study completion, and 156 were terminated from the study for other reasons. Significant clinical predictors of treatment failure (p < 0.05) included baseline anxiety symptoms, functional impairments, negative life events and lifetime clinical features such as a history of migraine, suicidal ideation/attempts, and mixed episodes, as well as a chronic course of illness.ConclusionsIn this PGBD Study of lithium response, several clinical features were found to be associated with failure to respond to lithium. Future validation is needed to confirm these clinical predictors of treatment failure and their use clinically to distinguish who will do well on lithium before starting pharmacotherapy.

Overexpression and long terminal repeat (LTR) polymorphism of the HRES‑1/Rab4 human endogenous retrovirus locus have been associated with T cell activation and disease manifestations in systemic lupus erythematosus (SLE). Although genomic DNA methylation is diminished overall in SLE, its role in HRES-1/Rab4 expression is unknown. Therefore, we determined how lupus-associated polymorphic rs451401 alleles of the LTR regulate transcription from the HRES-1/Rab4 promoter and thus affect T cell activation. The results showed that cytosine –119 is hypermethylated while cytosine –51 of the promoter and the LTR enhancer are hypomethylated in SLE. Pharmacologic or genetic inactivation of DNA methyltransferase 1 augmented the expression of HRES-1/Rab4. The minimal promoter was selectively recognized by metabolic stress sensor NRF1 when cytosine –119 but not cytosine –51 was methylated, and NRF1 stimulated HRES-1/Rab4 expression in human T cells. In turn, IRF2 and PSIP1 bound to the LTR enhancer and exerted control over HRES-1/Rab4 expression in rs451401 genotype– and methylation-dependent manners. The LTR enhancer conferred markedly greater expression of HRES-1/Rab4 in subjects with rs451401CC over rs451401GG alleles that in turn promoted mechanistic target of rapamycin (mTOR) activation upon T cell receptor stimulation. HRES-1/Rab4 alone robustly activated mTOR in human T cells. These findings identify HRES-1/Rab4 as a methylation- and rs451401 allele–dependent transducer of environmental stress and controller of T cell activation.