Citations

PURPOSE Social determinants of health (SDOH) shape cancer treatment access, adherence, and outcomes, yet their collection and use within National Clinical Trials Network (NCTN) studies remain poorly defined. This study examined how demographic and SDOH-related variables were historically collected and published to identify gaps that constrain the study of social context within NCTN trials. METHODS Participant-level data from completed phase III trials for gastrointestinal (GI) cancers conducted by the Alliance for Clinical Trials in Oncology (Alliance) or its legacy groups from 1999 to 2018 were pooled. Thirteen measures were assessed: four demographic and nine SDOH-related. The proportion of individual participants with data collected for each measure was evaluated. Data utilization was evaluated for all primary articles and via targeted review of related publications using the number either reporting subgroups or publishing analyses for each measure. RESULTS A total of 12,701 participants across 11 trials were included. All trials collected demographic measures (<2% of patients missing), insurance status (1% missing), and ZIP code (3% missing). Education level was collected in two trials (28% missing) with marital and employment status collected in one trial (41% missing for both). No trials collected data on other SDOH-related measures. Education level was the only SDOH-related measure reported in primary articles, and none reported analysis of SDOH-related measures. Of the 149 related publications, <2% reported or analyzed any SDOH-related measure. CONCLUSION Across Alliance and NCTN legacy group phase III trials for GI cancers, demographic variables have been consistently collected and frequently reported or analyzed, whereas SDOH-related measures are inconsistently collected and rarely published in the literature. These findings demonstrate a historical absence of routine SDOH data capture and utilization within NCTN trials.

Synaptic transmission can be tuned through plasticity mechanisms that regulate synaptic strength, structure, and number. In vivo measurements demonstrate remarkable spine dynamics, with subsets of synapses persisting for months. This correlates with the longevity of certain memories, which can persist for an organism’s lifetime. The molecular basis supporting the long-term stability of specific synapses and the long-term durability of memories remains unknown. At the protein level, most proteins persist for a relatively short amount of time before they are degraded and replaced with new molecules. However, recent work has identified a population of proteins, including those present at the synapse, that are exceptionally long-lived. It has been speculated that long-lived proteins (LLPs) could contribute to long-term synapse stability, function, and memory. Here, we used stable isotope labeling in mammals to first identify LLPs in the post synaptic density (PSD) of the hippocampus and subsequently determine if protein turnover rates varied by sex or following learning. We identified synaptic LLPs and found that both sex and experience can regulate synaptic protein turnover rates. We identified sex-dependent changes in protein turnover rates in autism spectrum disorder risk genes, including increased stability of Gabrg2, a GABA-A receptor subunit, in male mice. Furthermore, we observed stabilization of a subset of PSD proteins, such as Shank3, following contextual fear conditioning. We propose that sex- and experience-dependent changes in protein turnover rates could help explain sex-differences in psychiatric risk and aid our understanding of the molecular mechanisms that support learning and memory.

Cytotoxic T cells produce the cytokine interferon-γ (IFN-γ). We sought to determine whether IFN-γ directly kills target cells and found that T cells used IFN-γ to kill murine melanoma cells lacking the kinases TBK1 and IKKε. In the absence of both kinases, IFN-γ induced the production of TNF receptor 1 (TNFR1) and the sensor Z-DNA binding protein 1 (ZBP1) in the tumor cells to stimulate receptor-interacting protein kinase 1 (RIPK1)–dependent apoptosis in a cell-autonomous manner. IFN-γ also enhanced the activation of nuclear factor κB (NF-κB) signaling in a TNFR1-dependent manner in cells deficient in both TBK1 and IKKε. Because IFN-γ–induced apoptosis occurred in a transcription-dependent manner with slow kinetics, STAT1 and NF-κB cooperated to activate the expression of inflammatory genes in the dying cells. Thus, IFN-γ–induced cell death was accompanied by an inflammatory signature in the absence of TBK1 and IKKε. TBK1 and IKKε not only mediated the induction of type I IFN but also inhibited RIPK1-dependent death and NF-κB–dependent inflammation. Therefore, we propose that these kinases may have gained these intertwined functions so that cells infected by pathogens that produce antagonists of TBK1 and IKKε are eliminated by IFN-γ–secreting T cells in an inflammatory manner to compensate for the inhibition of type I IFN production.

Objectives Comparing clinical outcomes after cardiopulmonary bypass with hemodsorption (HA) versus cardiopulmonary bypass without HA in patients undergoing cardiac surgery in terms of mortality and major complications. Methods PubMed, Scopus, and Web of Science databases were searched for relevant randomized control trials (RCTs) that compared postoperative clinical outcomes between patients receiving intraoperative HA with cardiopulmonary bypass versus patients receiving cardiopulmonary bypass without intraoperative HA in cardiac surgery. Results Sixteen RCTs with 851 patients (433 in the HA group and 418 in the control group), were included in our meta-analysis. Our meta-analysis found no significant differences between the intraoperative HA group and the control group in patients undergoing cardiac surgery in terms of 30-days/in-hospital mortality, new-onset atrial fibrillation, stroke or cerebrovascular events, postoperative delirium, renal failure/acute kidney injury, need for renal replacement, postoperative liver dysfunction, thrombocytopenia, bleeding, volume of blood loss, pneumonia, sepsis, respiratory insufficiency, duration of postoperative ventilation, distributive/septic shock, pericardial tamponade, need for extracorporeal membrane oxygenation (ECMO) support, sequential organ failure assessment (SOFA) score at ICU admission, plasma-free hemoglobin levels, and fibrinogen levels. However, the pooled analysis showed a significant association between HA and decreased albumin at ICU admission (MD = − 0.28, 95% CI [0.55 to 0.01], p -value = 0.04), decreased length of ICU stay (MD = −0.66, 95% CI [−1.24 to 0.08], p -value = 0.03), and decreased length of hospital stay (MD = −0.99, 95% CI [−1.88 to −0.10], p -value = 0.03). Conclusion Our findings suggest that there is not enough evidence to endorse the role of routine intraoperative HA during cardiopulmonary bypass in improving clinical outcomes after cardiac surgery. Factors such as patient risk profile, procedure complexity, and cost implications should be taken into account when considering this adjunct therapy.

Our research uncovers a role for ATR in responding to ECM stiffness and promoting epithelial-to-mesenchymal transition (EMT) and metastasis. ATR, when deubiquitinated and upregulated by USP21 under enhanced ECM stiffness conditions, phosphorylates the nuclear protein SUN2, which promotes β-catenin nuclear translocation and EMT. ATM-mediated EMT promotes polymorphonuclear myeloid-derived suppressor cell recruitment and inhibits CD103 + dendritic cells, fostering an immunosuppressive tumor milieu. ATR inhibition disrupts this malignant cascade by promoting mesenchymal-to-epithelial transition to enhance antitumor immunity and mitigate metastases. Consistently, circulating HLA-DR + dendritic cells were also enhanced following treatment with the ATR inhibitor berzosertib in patients with therapeutically resistant early-stage breast cancer. Our data suggest that ATR-targeted therapy may be optimized by considering both DNA damage–dependent and EMT-inducing effects of ATR ATR promotes metastasis and immunosuppression through EMT process

Importance Opioid prescribing has decreased in the US for more than a decade. However, less is known about how prescribing trends differ by prescriber specialty and separately for short-term and long-term opioid prescribing for which the indications, clinical decision-making, and potential for harm vary substantially. Objective To characterize opioid analgesic prescribing trends in the US between January 1, 2010, and December 31, 2024, by prescriber specialty, analyzing short-term and long-term opioid use episodes separately. Design, Setting, and Participants This cross-sectional study used administrative claims data for commercially insured and Medicare Advantage patients (aged ≥65 years and &amp;lt;65 years with long-term disability) with at least 90 days of enrollment in medical and prescription coverage. Statistical analysis was performed from May 2025 to September 2025. Main Outcomes and Measures Prescribing volume, daily dose, and prescription duration. Results The study identified 110 288 218 opioid fills by 14 959 612 patients during the 15-year study period. Among opioid fills, 59.4% were attributed to female patients; the median (IQR) age at opioid fill was 61 (50-71) years. From 2010 to 2024, decreases in opioid prescribing were greater for long-term than short-term opioid use episodes (eg, commercial cohort: 81.3% reduction [from 33.2 fills per 100-person years in 2010 to 6.2 in 2024] and 74.6% reduction [from 36.2 fills per 100-person years in 2010 to 9.2 in 2024]), respectively. The proportion of all opioid fills written by primary care clinicians decreased (eg, Medicare Advantage with disability cohort: from 52.2% to 47.2%), whereas those written by pain medicine specialists increased (eg, Medicare Advantage with disability cohort: from 17.1% to 25.7%). Distinct trends for short-term and long-term opioid use episodes were observed in prescription characteristics, such as daily dose and duration. Conclusions and Relevance In this cross-sectional study of opioid prescribing trends in the US between 2010 and 2024, decreases in prescribing were greatest in long-term opioid use episodes, and prescribing was increasingly concentrated among pain medicine specialists. These findings suggest the need to balance reductions in opioid prescribing with provision of nonopioid pain treatments and raise concerns about access to care for patients taking opioids for chronic pain management.