COVID-19 vaccination is a key determinant for optimizing booster strategies in older adults, who remain at high risk for severe outcomes because of immunosenescence and waning immunity. We previously reported neutralizing responses in a prospective cohort of 90 older adults ( ≥ 65 years) at 6 months after boosting with trivalent (Tri-XBB.1.5), bivalent (Bi-Omi-XBB), or tetravalent (Tetra-XBB.1) protein vaccines. 1 In this extended follow-up to 12 months post-vaccination of the same cohort, we assessed neutralizing antibody persistence, decay kinetics, and protective effectiveness against SARS-CoV-2 infection. Detailed methods are provided in the Supplementary Materials.Allparticipants, regardless of infection status after booster vaccination, maintained detectable neutralizing antibodies across the three vaccine cohorts at 12 months post-booster (Fig. 1a, b), with comparable geometric mean titers (GMTs, all p > 0.05). In the Tri-XBB.1.5 cohort (Fig. 1a), the GMTs on day 357 ranged from 313.1 (XEC) to 3,583.0 (BA.5). Compared with day 185, signi fi cant declines were observed for all the variants except D614G, with GMT reductions of 1.7-fold for BA.5, 1.3-fold for XBB.1.5, 1.6-fold for JN.1, 1.2-fold for KP.3, and 1.9-fold for XEC. In the Bi-Omi-XBB cohort (Fig. 1a), the GMTs on day 357 ranged from 452.6 to 2047.0; signi fi cant declines were observed for BA.5 (3.2-fold), XBB.1.5 (2.
Antibody-drug conjugates (ADCs) have expanded treatment options across multiple malignancies, but their clinical benefit remains constrained by heterogeneous and sometimes serious toxicities. These toxicities rarely arise from a single component; instead, they reflect the association between target biology, molecular architecture, systemic exposure, and tissue susceptibility. We first examine the structural basis of ADC toxicity by discussing the distinct contributions of the antibody–target axis, linker, payload, drug loading, and conjugation strategy to systemic exposure and tissue toxicity. We distinguish organ-selective “on-target, off-tumor” injury from target-independent toxicity and further characterize two major off-target routes: context-dependent uptake of intact ADCs through Fcγ receptor-mediated or pinocytosis-dominant pathways, and spatially distinct exposure to released payload arising from premature systemic release or localized bystander diffusion. Furthermore, we summarize a multidisciplinary management framework, ranging from prophylactic measures to graded interventions across complex scenarios such as treatment rechallenge and combination therapy. Finally, we discuss strategies to widen the therapeutic window through exposure-response-guided dosing, next-generation molecular engineering, and emerging conjugate platforms. Artificial intelligence and computational approaches may further extend safety optimization from drug design to patient stratification and real-world surveillance. By linking molecular design, spatial exposure, and clinical management, this review provides an integrated framework to improve ADC safety while preserving antitumor efficacy.
In a recent study published in Science, Lian et al. shed light on a previously unrecognized mechanism of CD4 T cell-mediated control of tumor growth that does not require direct tumor cell recognition and can operate independently of interferon (IFN) γ , relying instead on stromal remodeling and destruction of tumor-associated vessels. 1 Although cancer immunotherapy is often framed around cytotoxic lymphocytes directly recognizing malignant cells, CD4 ⁺ T cells can also reshape the tumor microenvironment (TME) through cytokine-driven interactions with stromal and immune compartments. In cancer, CD4 ⁺ T cells promote priming (e.g. dendritic cell licensing) and effector phases of tumor-speci fi c immune responses by locally establishing tertiary lymphoid structures and releasing soluble mediators [e.g., IFN γ and tumor-necrosis factor (TNF)- α ], which in turn promote antigen presentation on tumor cells, sustain cytotoxic T cell in fi ltration, fi tness, and tumor killing, as well as shift myeloid cells polarization towards an in fl ammatory and tumoricidal phenotype. In addition, CD4 + T lymphocytes can directly kill tumor cells by recognizing cognate peptide antigens presented by major histocompatibility complex II (MHC II) via T-cell receptor (TCR) engagement. Accordingly, the presence of effector CD4 ⁺ tumor-in fi ltrating lymphocytes (TILs) has been associated with favorable outcomes in several settings. 2 Whether these stroma-remodeling functions can be organized into a therapeutically relevant mechanism of tumor control still represents an unresolved question. Lian and colleagues employed different transplantable solid tumor models (colon, breast, and melanoma) engineered to express MHC-II-restricted antigens recognized by
Epilepsy is one of the most prevalent and disabling neurological disorders, affecting >50 million people worldwide. Beyond recurrent seizures, it is strongly associated with cognitive impairment, psychiatric comorbidities, reduced social participation, and a markedly increased risk of premature death. Although considerable advances in neuroimaging, pharmacology, and surgical techniques have expanded therapeutic possibilities, nearly one-third of patients remain refractory to current treatments, a challenge that highlights the pressing need for deeper mechanistic insights and innovative therapeutic strategies. This review provides an integrated overview of recent progress in epilepsy research and treatment. At the molecular level, we examine how ion channel dysfunction, receptor abnormalities, and disrupted signaling pathways drive hyperexcitability. We highlight insights from genetics and acquired etiologies that illuminate disease heterogeneity. We address prevailing hypotheses of drug resistance and potential biomarkers. We also emphasize the growing recognition of epilepsy’s close association with diverse comorbidities, where shared molecular pathways not only deepen our understanding of disease mechanisms but also highlight new therapeutic targets. Finally, we evaluate emerging therapeutic directions, including precision pharmacology, neuromodulation, gene and cell therapies, and metabolic approaches such as the ketogenic diet. By bridging epidemiological perspectives with mechanistic discoveries and innovative therapies, this review underscores how advances in epilepsy research are reshaping the path toward precision medicine and improved patient outcomes.
Oculo-Cerebro-Renal-Lowe syndrome, caused by loss of the PI(4,5)P₂ 5-phosphatase OCRL, is a rare and severe disorder that lacks curative therapy. By integrating deep cell-biological insight into endosomal trafficking and proximal tubule protein reabsorption with high-content screening across engineered cell lines, patient-derived proximal tubule cells, human kidney organoids, and a humanized mouse model, we identify IB-MECA, an oral adenosine A3 receptor agonist, as a targeted therapy poised for clinical evaluation. IB-MECA normalizes endosomal PI(4,5)P₂ homeostasis, restores receptor trafficking, and rescues protein reabsorption in all systems, demonstrating the translational power of a mechanism-anchored, cross-species screening pipeline that couples cellular correction to organ-level benefit and supports rapid progression toward phase II testing pending regulatory approval. Mechanistic dissection revealed that IB-MECA acts through A3AR-dependent activation of PLC, revealing a previously unrecognized axis whereby receptor-driven hydrolysis of plasma-membrane PI(4,5)P₂ corrects pathological endosomal PI(4,5)P₂ accumulation. This receptor-mediated rewiring of phosphoinositide homeostasis contrasts with earlier strategies based on broad kinase inhibition and establishes plasma-membrane GPCR–PLC signaling as a precise, druggable entry point to correct endolysosomal lipid imbalance. Together with the favorable clinical safety record of IB-MECA, these findings provide a compelling rationale for an imminent clinical trial (NCT07410455) in Lowe syndrome and outline a generalizable, cell biology–guided framework for developing therapies for inherited disorders of phosphoinositide metabolism.
