Yong Won Choi

Liquid–liquid phase separation (LLPS) is essential for proper DNA damage signaling. The sequential formation of PAR‐ and 53BP1‐based condensates must be tightly controlled in space and time, however the molecular regulators of this process remain insufficiently defined. Here, we show that RSF1 contains a substantial proportion of intrinsically disordered regions (IDRs) and participates in the sequential assembly of liquid condensates at DSB sites. RSF1 depletion severely abolishes 53BP1 optoDroplet formation without affecting FUS condensates, but causes persistent PAR chains due to defective PARG recruitment. Domain mapping reveals that the C‐terminal region of the IDR in RSF1 is sufficient to support 53BP1 condensate formation. Mechanistically, RSF1 controls the timely extinction of PAR chains by promoting the recruitment of PARG, but not PARP1, to DNA damage sites. This regulation enables the transition from PAR‐based scaffolds to 53BP1 condensates. Importantly, defects in RSF1‐mediated condensate formation correlate with impaired transcription of p53 target genes, including p21CIP1. Together, these findings establish RSF1 as a molecular coordinator that links PAR turnover to 53BP1 condensate assembly, thereby coupling the spatial and temporal regulation of LLPS with p53‐dependent transcriptional responses at DNA lesions.

For over two decades, the standard of care for resectable locally advanced head and neck squamous cell carcinoma (LA-HNSCC) has remained radical surgery followed by risk-adapted adjuvant therapy. Despite this, high-risk patients experience significant relapse; in particular, current adjuvant concurrent chemoradiotherapy regimens fail to adequately control distant metastasis. Preclinical studies suggest that neoadjuvant immune checkpoint inhibitor (ICI) induces superior antitumor immunity compared to adjuvant therapy by leveraging the primary tumor as an antigen source for systemic T-cell priming. Phase II data further indicate that neoadjuvant ICI, either as monotherapy or in combination, can enhance pathological response rates without compromising surgical safety. Building on these findings, recent two pivotal Phase III KEYNOTE-689 and NIVOPOSTOP confirmed the definitive roles of perioperative immunotherapy. KEYNOTE-689 demonstrated that neoadjuvant-adjuvant pembrolizumab significantly improves event-free survival, primarily by reducing distant recurrence. Conversely, the NIVOPOSTOP trial, which utilized only adjuvant/concomitant nivolumab, showed significant improvement in disease-free survival driven by locoregional control but failed to significantly impact distant relapse. Perioperative ICI represents a transformative shift in LA-HNSCC management. The contrasting results of KEYNOTE-689 and NIVOPOSTOP highlight that the neoadjuvant window is critical for systemic disease control via immune priming. Future strategies will shift away from “one-size-fits-all” models toward risk-stratified, response-adapted approaches. Landmark trials in melanoma, which proved that extensive lymph node dissection can be safely omitted in patients with favorable pathologic responses, provide a blueprint for using pathological response as a surrogate marker to guide treatment de-escalation, aiming to maximize survival while preserving organ function and quality of life in LA-HNSCC.

Background and Objectives: Cancer patients are particularly susceptible to infections caused by multidrug-resistant Gram-negative bacteria (MDR GNB) due to chemotherapy- or radiation therapy-induced immunosuppression. Colistin is often prescribed as a last-resort agent for MDR GNB infection, but its clinical benefit in oncology patients remains unclear. This study aims to evaluate the mortality risk associated with colistin versus non-colistin regimens in cancer patient with MDR GNB infections, stratified by resistance profiles, infection sites, and concomitant medication use. Materials and Methods: A retrospective cohort study was conducted in adult cancer patients with MDR GNB infections that are resistant to at least three antibiotic classes and identified from at least two anatomical sites at a tertiary care hospital in Korea. Propensity score-matched in a 1:3 ratio either to the colistin group or non-colistin group and multivariate Cox hazard regression analyses were used to evaluate mortality in cancer patients with MDR GNB infections, primarily Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Results: A total of 85 patients (29 patients in the colistin and 56 patients in the non-colistin group) were included in the analysis. Overall, colistin use did not show a statistically significant mortality benefit compared to non-colistin regimens (hazard ratio (HR) 0.93, 95% CI 0.47–1.87). However, the subgroup analysis revealed that colistin had a potential association with significantly lower mortality in pneumonia patients with aminoglycoside-resistant infections (HR 0.04, 95% CI 0.002–0.69). Concomitant use of antipsychotics and benzodiazepines in selected resistance profiles also correlated with improved outcomes. In contrast, a potential association was found between concomitant macrolide use and increased mortality in patients with fluoroquinolone- or penicillin-resistant profiles. Conclusions: Colistin may offer survival benefits in selected high-risk cancer patients with MDR GNB pneumonia. Treatment outcomes are influenced by resistance profiles, infection sites, and concomitant medications, indicating the significant importance of individualized antimicrobial therapy and antimicrobial stewardship in oncology patients.

Since therapy‐induced senescence (TIS) can either support or inhibit cancer progression, identifying which types of chemotherapeutic agents can produce the strongest anti‐tumor TIS is an important issue. Here, cyclin‐dependent kinase4/6 inhibitors (CDK4/6i)‐induced senescence was compared to the TIS induced by conventional DNA‐damaging agents. Despite both types of agents eliciting a similar degree of senescence, we observed increased expression of the senescence‐associated secretory phenotype (SASP) and ligands related to pro‐tumor immunity (IL6, CXCL8, TGFβ, CD274, and CEACAM1) and angiogenesis (VEGFA) mainly in TIS induced by DNA‐damaging agents rather than by CDK4/6i. Additionally, although all agents increased the expression of anti‐tumor immunomodulatory proteins related to antigen presentation (MHC‐I, B2M) and T cell chemokines (CXCL9, 10, 11), CDK4/6i‐induced senescent cells still maintained this expression at a similar or even higher intensity than cells treated with DNA‐damaging agents, despite the absence of nuclear factor‐kappa‐B (NF‐κB) and p53 activation. These data suggest that in contrast with DNA‐damaging agents, which augment the pro‐tumorigenic microenvironment via pro‐inflammatory SASP, CDK4/6i can generate TIS only with antitumor immunomodulatory proteins.

Accumulating evidence indicates a link between diabetes and cancer. Selective estrogen receptor modulators (SERMs) may increase diabetes risk via antiestrogen effects. This study investigated incident diabetes risk of SERM treatment and its effects on metastatic cancer and death prevention in breast cancer survivors. This retrospective cohort study included female patients with early-stage breast cancer, treated with or without SERMs, between 2008 and 2020 in a tertiary care hospital in Korea. Four propensity score-matched comparison pairs were designed: SERM use versus non-use, long-term use (≥1500 days) versus non-use, tamoxifen use versus non-use, and toremifene use versus non-use; then, logistic regression analysis was performed for risk analysis. SERMs in general were not associated with an elevated risk of diabetes; however, when used for ≥1500 days, SERMs—especially toremifene—substantially increased diabetes risk in breast cancer patients (OR 1.63, p = 0.048). Meanwhile, long-term SERM treatment was effective at preventing metastatic cancer (OR 0.20, p < 0.001) and death (OR 0.13, p < 0.001). SERM treatment, albeit generally safe and effective, may increase diabetes risk with its long-term use in women with breast cancer. Further studies are required to verify the association between toremifene treatment and incident diabetes.

Choi YW, et al. J Korean Med Sci. 2015 Oct;30(10):1416-1422. http://dx.doi.org/10.3346/jkms.2015.30.10.1416

Choi YW, et al. J Korean Med Sci. 2014 Nov;29(11):1493-1500. http://dx.doi.org/10.3346/jkms.2014.29.11.1493