Citations

In the host immune system, cytotoxic T cells (CTLs) play a critical role in mounting an effective attack against tumorigenic cells. CTLs can drive this immunity through two mechanisms: direct lysis of tumor cells via cytolytic granule release and secretion of inflammatory cytokines such as interferon-γ (IFN-γ). While IFN-γ is well known for its role in upregulating major histocompatibility complex (MHC) class I presentation and differentiating naïve T cells into T helper 1 cells, its role in direct killing of tumor cells is less understood. In a recent study, we found that tumor cells lacking the signaling kinases TANK-binding kinase 1 (TBK1) and inhibitor of κB kinase ε (IKK-ε) were more easily killed by IFN-γ-producing T cells than their wild-type counterparts. In the absence of both kinases, IFN-γ upregulated the expression of both tumor necrosis factor receptor 1 (TNFR1) and the left-handed nuclei acid sensor Z-DNA-binding protein 1 (ZBP1) to trigger cell-autonomous apoptosis. Loss of TBK1 and IKK-ε also heightened nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) activation downstream of IFN-γ, along with increased production of inflammatory chemokines and cytokines. Thus, IFN-γ-induced death was paired with an inflammatory environment when the two kinases were absent. Our study illustrates that TBK1 and IKK-ε not only have a role in mediating a type I IFN response but also in regulating IFN-γ-induced death and NF-κB-dependent inflammation. Herein, we briefly highlight how the wiring of these kinases may have evolved over time to combat opportunistic pathogens and how this may shape our approach to cancer immunotherapy.

ABSTRACT Microplastic pollution may influence neurodevelopment, yet its relationship with attention‐deficit/hyperactivity disorder (ADHD) remains unclear. We integrated a pediatric cohort, multi‐omics analyses, network toxicology, and animal experiments to investigate polyethylene (PE) microplastic exposure in ADHD vulnerability. Among 90 children, PE was the predominant polymer detected in blood and was more abundant in children with ADHD. Higher PE burden was associated with greater symptom severity, increased IL‐6, and reduced antioxidant capacity. Multi‐omics and network analyses converged on PI3K/AKT1/Nrf2 signaling. In a perinatal nicotine mouse model, developmental PE co‐exposure exacerbated ADHD‐like behaviors, dopaminergic dysfunction, and oxidative injury. Melatonin partially alleviated these abnormalities by restoring PI3K/AKT1/GSK3β and Nrf2 signaling, whereas AAV‐mediated PI3K knockdown weakened its protective effects. Collectively, the human findings identify circulating PE burden as an environmental correlate of ADHD‐related neurodevelopmental vulnerability, while the animal experiments provide evidence that developmental PE co‐exposure can aggravate ADHD‐like abnormalities in a susceptible background.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited disorder leading to kidney failure. Tolvaptan, the only FDA-approved therapy, modestly slows disease progression but is limited by significant adverse effects, highlighting the need for more effective and better-tolerated treatments. Ciliary polycystins are central to ADPKD pathogenesis. We previously demonstrated that a cilia base-localized pool of CDK6 restricts ciliary polycystin abundance by suppressing axonemal polyglutamylation. However, whether CDK6 inhibition can restore polycystin function and suppress ADPKD progression in vivo remains unknown. Methods: Abemaciclib was tested in in vitro 3D cyst assays and ex vivo metanephric organ cultures. In vivo efficacy of early- and late-stage intervention were assessed in F1(129/B6) Pkd1 R3277C/R3277C mice receiving daily abemaciclib. Tolvaptan served as a therapeutic control. Cyst burden, fibrosis in the kidneys, kidney function, and primary cilia of renal epithelial cells were analyzed at study endpoints. Results: CDK6 was prominently upregulated in cyst-lining cells in human and murine PKD kidneys. At doses substantially lower than those used in oncology, abemaciclib robustly suppressed cyst growth in vitro and ex vivo . In vivo , long-term early treatment arrested cyst progression more effectively than tolvaptan without detectable toxicity. Late intervention largely halted cyst growth in females and reversed cyst progression in males. Mechanistically, abemaciclib restored axonemal polyglutamylation and increased ciliary polycystin levels. Conclusions: Abemaciclib has greater therapeutic efficacy and tolerability than tolvaptan in this preclinical model, largely driven by CDK6 inhibition–mediated restoration of axonemal polyglutamylation and increased ciliary polycystin abundance.

Abstract Therapeutic resistance in ovarian cancer is frequently driven by persistent replication stress, yet the molecular mechanisms that convert replication stress into a therapeutically exploitable vulnerability remain incompletely understood. Here, we identify drug-induced nuclear cathepsin L (nCTSL) as a previously unrecognized regulator of replication stress and DNA repair. Clofarabine (CLF) combined with the ATR inhibitor AZD6738, or the CHK1 inhibitor prexasertib promoted nuclear accumulation of CTSL, where it remodeled the replication machinery through degradation of CCNE1, MCM3, MCM6, and geminin, accompanied by loss of RAD51 and 53BP1 and increased γH2AX and phospho-RPA2. DNA fiber analysis demonstrated marked inhibition of replication fork progression following CLF-based combinations, whereas CTSL depletion accelerated fork progression and abolished therapy-induced replication stress. Reconstitution with the nuclear M1F CTSL isoform restored replication restraint, confirming a direct role for nuclear CTSL in regulating replication dynamics. GFP-based DNA repair reporter assays further revealed that CLF-based combinations suppress DNA repair competence in a CTSL-dependent manner, indicating that nuclear CTSL couples replication stress amplification with functional inhibition of repair pathways. Functionally, CLF-based combinations selectively targeted transformed fallopian tube secretory epithelial cells while sparing non-transformed counterparts, demonstrated broad activity in patient-derived ovarian cancer ascites spheroids, and significantly inhibited tumor growth and prolonged survival in vivo . Collectively, our findings identify nuclear CTSL as a mechanistic driver of replication stress that remodels the replication machinery, impairs DNA repair, and creates a therapeutically exploitable vulnerability in ovarian cancer. We propose that nuclear CTSL promotes a transition from replication competence to replication catastrophe, thereby establishing a conceptual framework for biomarker-guided therapeutic strategies targeting CTSL-dependent replication stress.

Background and Objectives: Normothermic regional perfusion (NRP) is an effective technique to improve recipient outcomes. However, no valid methods for determining liver viability exist. Identifying relevant biological markers with clinical correlation to liver viability and recipient clinical outcomes is imperative to improve decision-making. Materials and Methods: Fifty-four donors undergoing NRP and their recipients were included. FMN was measured at the start, 1 h, and end of NRP. Lactate was measured at the start, 30, 60, and 90 min of NRP. Primary outcomes were early allograft function using the early allograft dysfunction (EAD) criteria and the model for early allograft function (MEAF). Secondary outcomes included the association with donor warm ischemia time (DWIT), stratified by 30 min. Spearman’s rho assessed correlations. Results: Forty (74%) livers were transplanted, with 5 (12.5%) recipients developing EAD and the mean MEAF score was 3.13 (1.49). FMN at all time points was significantly greater in the EAD group compared to the non-EAD group and was significantly correlated with the MEAF score (Peak FMN: rho = 0.507, p = 0.001). FMN during perfusion did not differ between DWIT < and ≥30 min. Lactate levels were similar across all groups and did not discriminate for adverse allograft outcomes. However, lactate levels during perfusion were higher in the DWIT ≥ 30 min group. Conclusions: These findings suggest that during NRP, elevated FMN, but not lactate, is associated with early allograft function.

Alcohol-associated liver disease (ALD) is a growing global health concern, with alcohol-associated hepatitis (AH) leading to the highest morbidity and mortality. Available therapies are limited and often inadequate. Platelets contribute in a variety of ways to liver disease pathogenesis, but their role in AH remains largely unexplored. In this study, we addressed the hypothesis that platelets contribute to pathological inflammation in AH. Using patient samples and a multiomics approach, we found that platelets undergo proinflammatory transcriptomic and proteomic changes in AH, with 2 alarmins, S100A8 and S100A9, being among the top upregulated genes/proteins. Additionally, the abundance of platelet-derived microparticles containing S100A8 and S100A9 in AH patient plasma was increased and correlated with disease severity (assessed by model for end-stage liver disease sodium [MELD-Na]) and endotheliopathy (assessed by ICAM1, CXCL8, and vWF). We mechanistically linked S100A9 with endotheliopathy via crosstalk between primary human liver sinusoidal endothelial cells and primary human monocytes. We also demonstrated that IL-6 upregulates S100A9 in megakaryocytic cells in a JAK/STAT-dependent manner, modeling changes occurring in the bone marrow in patients with AH. Our studies establish proinflammatory platelets as important contributors to AH pathology. Moreover, antiplatelet agents — or, more specifically, S100A9 targeted drugs — are potential therapeutic strategies in AH.

Introduction Antibody–drug conjugates (ADCs) are now widely used in breast cancer across multiple disease subtypes. With increasing clinical use, treatment-related toxicities have become an important factor in therapeutic decision-making. However, comparative safety data among ADCs are limited because direct head-to-head trials are lacking. Methods We conducted a systematic review and Bayesian network meta-analysis of randomized controlled trials evaluating ADCs in breast cancer, with the literature search updated through March 31, 2025. Treatment-related adverse events (TRAEs) and serious adverse events (SAEs) were classified according to the Common Terminology Criteria for Adverse Events. A Bayesian random-effects network meta-analysis was used to compare toxicity risks across regimens. Odds ratios (ORs) with 95% credible intervals (CrIs) were estimated, and surface under the cumulative ranking curve (SUCRA) values were used as descriptive ranking summaries interpreted alongside the corresponding comparative estimates. The protocol was registered in PROSPERO (CRD42024606194). Results Seventeen randomized trials including 8,946 patients and five ADCs—trastuzumab emtansine (T-DM1), sacituzumab govitecan (SG), trastuzumab deruxtecan (T-DXd), datopotamab deruxtecan (Dato-DXd), and ARX788—were analyzed. SG and T-DXd showed the least favorable hematologic safety profiles, with SUCRA values for anemia/neutropenia of 22.6%/17.4% and 12.0%/27.0%, respectively. T-DM1-based regimens had the highest risk of thrombocytopenia. For gastrointestinal toxicities, SG ranked worst for diarrhea (SUCRA 6.0%), whereas T-DXd was associated with higher risks of nausea (2.2%), vomiting (7.9%), and decreased appetite (8.6%). In analyses of SAEs, SG had the highest rates of anemia (11.7%) and neutropenia (8.5%), while gastrointestinal SAEs occurred more frequently with T-DXd. Conclusions This network meta-analysis highlights clinically meaningful differences in ADC safety profiles and may help guide individualized toxicity management in breast cancer.

Background/Objectives: The objective of this study was to evaluate age-specific effects of intraoperative platelet-rich plasma (PRP) administration on postoperative pain, wound healing, and bleeding after tonsillectomy. Methods: PubMed, Embase, Scopus, Google Scholar, and Cochrane databases were searched from inception to October 2025. Randomized controlled trials comparing intraoperative PRP with placebo or no treatment in patients undergoing tonsillectomy were included. Data on postoperative pain, wound healing, and bleeding were extracted and analyzed using standardized mean differences (SMDs) and odds ratios (ORs) with 95% confidence intervals (CIs). Subgroup analyses were performed by age (adults versus children) and by postoperative day. Results: Nine randomized controlled trials comprising 442 participants were included. In adults, PRP significantly reduced postoperative pain (SMD = −1.26 [−1.70 to −0.81]) and improved wound healing (SMD = −1.43 [−2.65 to −0.22]). The analgesic effect was greatest during the early recovery period (postoperative days 0–5) and diminished thereafter. There were no significant differences in primary postoperative bleeding (OR = 0.49 [0.04 to 5.61]) or secondary postoperative bleeding (OR = 0.23 [0.02 to 2.16]) between the PRP and control groups. In children, PRP did not significantly affect pain or bleeding outcomes. Conclusions: Intraoperative PRP may reduce early postoperative pain and may promote mucosal recovery in adults. However, its clinical efficacy in children remains unclear. Further well-designed, age-stratified trials are warranted to clarify the role of PRP in enhancing postoperative recovery.