Severe trauma is a leading cause of mortality worldwide; however, contemporary data on mechanism-specific incidence trends and factors associated with in-hospital mortality remain limited. We conducted a nationwide cohort study using a South Korean severe trauma registry spanning 2016 to 2024. Severe trauma was defined as an Injury Severity Score (ISS) ≥ 16. Annual incidence trends were assessed using negative binomial regression with incidence rate ratios (IRRs) and 95% confidence intervals (CIs). Factors associated with in-hospital mortality were identified using multivariable logistic regression, performed separately for patients with and without prehospital cardiac arrest. A total of 73,232 patients were included, of whom 44.9% had prehospital cardiac arrest. Overall in-hospital mortality was 58.2% (26.0% vs 97.7% for patients without versus with prehospital cardiac arrest, respectively). Transport-related injuries were the most common (53.5%), followed by falls/slips (38.2%). Transport-related severe trauma declined by 3.6% annually (IRR, 0.964; 95% CI, 0.955-0.974; P < .001), whereas falls/slips increased by 3.7% annually (IRR, 1.037; 95% CI, 1.024-1.050; P < .001). Among patients without prehospital cardiac arrest, higher ISS (ISS 25-40: adjusted odds ratio [aOR], 3.45; 95% CI, 3.26-3.64; ISS 41-75: aOR, 6.12; 95% CI, 5.40-6.93) and older age (≥65 years: aOR, 2.87; 95% CI, 2.16-3.84) were the strongest independent predictors of in-hospital mortality. Male sex, unintentional injury, lower-level receiving emergency departments, and falls/slips as the injury mechanism (aOR, 1.19; 95% CI, 1.13-1.26) were also independently associated with increased mortality. Among patients with prehospital cardiac arrest, conventional trauma system factors lost prognostic significance; self-harm was the strongest independent predictor (aOR, 2.14; 95% CI, 1.53-3.08). Female sex and injury in nonmetropolitan areas were also independently associated with increased mortality. The epidemiology of severe trauma in South Korea is evolving, with transport-related injuries declining and falls/slips increasing. Preventive strategies for falls/slips should become a public health priority. Given the near-universal mortality among patients with prehospital cardiac arrest, in whom conventional trauma system factors lose prognostic significance, primary prevention strategies, including suicide prevention and injury awareness programs, may yield greater reductions in severe trauma mortality than trauma system development alone.

Type 2 long QT syndrome (LQT2) increases the risk of cardiac arrest and sudden death due to reduced rapid delayed rectifier potassium currents (IKr) in the heart. Caused by loss-of-function genetic variants in the hERG K+ channel, LQT2 might benefit from variant-targeted therapy approaches. T1019PfsX38 and Q1070X are LQT2-causing variants reported in Oman and Saudi Arabia. Although nonsense-mediated mRNA decay (NMD) has been proposed to contribute to reduced expression of these truncating variants, it remains unclear whether residual mutant hERG channel function can be pharmacologically enhanced. We used the patch-clamp technique and examined the effects of the hERG potentiator NS1643 on wild-type-, T1019PfsX38- and Q1070X-hERG channels expressed in HEK293 cells. We started by assessing the response of these variants under the influence of a ventricular action potential clamp protocol, then used additional protocols to elucidate the drug's mechanism of action. NS1643 [10 µM] enhanced the repolarization currents in wild-type-, T1019PfsX38- and Q1070X-expressing cells. Its effect was associated with accelerated activation rates and a negative shift in the voltage dependence of activation. In addition, NS1643 suppressed fast deactivation transitions. We conclude that the functions of T1019PfsX38- and Q1070X-hERG channels can be augmented by hERG potentiators if NMD is incomplete, which may facilitate the development of a mechanism-based rescue approach.

Activating mutations in KRAS drive pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC). Although mutant-selective KRAS inhibitors and pan-RAS inhibitors provide clinical benefits, the development of resistance limits durable responses. Here, transcriptomic and proteomic analyses revealed that, despite effective suppression of mutant KRAS signaling, resistant cells sustain cell cycle progression. Distinct orthogonal mitogenic pathways were engaged in a context-dependent manner to bypass KRAS inhibition. While these pathways could be broadly inhibited using the pan-RAS-ON inhibitor RMC-6236, cells remained capable of developing acquired resistance where cell proliferation was uncoupled from RAS signaling. Combinatorial drug screens and genome-wide CRISPR-Cas9 screens showed that perturbing cell cycle nodes via targeting cyclin dependent kinases CDK4/6 and CDK2 restored sensitivity to KRAS/RAS inhibitors. Co-targeting CDK4/6 induced G1 arrest and suppressed E2F-regulated proteins across all resistant models. In contrast, co-targeting CDK2 exerted a broader effect by impairing DNA replication, inducing G2 arrest, preventing mitotic entry, and yielding a more durable cytostatic response that delayed cellular outgrowth after drug withdrawal. Finally, concurrent inhibition of KRAS with either CDK4/6 or CDK2 yielded durable tumor control in vivo in xenografts derived from models with acquired resistance. In conclusion, these findings identify sustained cell cycle activity as a defining feature of resistance to KRAS-directed therapies and establish cell cycle co-targeting as an effective strategy to overcome KRAS/RAS inhibitor resistance.

UKALL14 (NCT01085617) T-cell arm was a phase 3, randomized-controlled trial. Adults aged 25-65 years were randomized 1:1 at entry to receive standard of care (SOC) or SOC + nelarabine 1.5 g/m[2] (Days 1, 3, and 5) to be administered following second induction. The primary end-point was event-free survival (EFS). From 2011 to 2018, 143 patients were randomly assigned to SOC (N = 75) or SOC + nelarabine (N = 68). There was no significant difference in EFS between the treatment groups; HR 0.86 (95% CI 0.52-1.43) P = 0.57, EFS: 58.2% SOC versus 62.7% SOC + nelarabine. The severe adverse events and nonrelapse mortality rates did not differ between the arms; in particular, there was no difference in grade 3-4 neurotoxicity. The 3-year cumulative incidence of relapse was 31% in the SOC arm versus 28.9% in the SOC+ nelarabine arm. Forty of 44 relapses (90.9%) occurred within 2 years of randomization; the median survival postrelapse was 5.7 months, with no difference by arm. Diagnostic samples were analyzed for level of differentiation arrest by analysis of the TCRg locus to detect the most immature cases through absence of biallelic TCRg deletion (ABD). There was a trend toward more relapses with ABD (37.3%) versus no ABD (19.5%), P = 0.066. Diagnostic samples (N = 133) were analyzed for mutations in NOTCH1, FBXW7, NRAS, KRAS, and PTEN, with no significant differences in CR rates or survival in patients with wild-type (WT) NOTCH1 or FBXW7. The 12 patients with NRAS mutations had significantly inferior CR and EFS compared to patients with wild-type NRAS.

Cellular senescence drives aging and age-related diseases, posing a critical barrier to stem cell-based regeneration. While selective elimination of senescent cells (senolysis) remains a theoretically promising strategy, safe natural senotherapeutic agents are limited. Human exfoliated deciduous tooth stem cells (SHED) possess high regenerative potential yet are vulnerable to senescence, compromising their therapeutic utility.

Cellular senescence is characterized by irreversible cell-cycle arrest, with cells remaining viable and metabolically active. This state features a proinflammatory senescence-associated secretory phenotype (SASP) that can harm neighboring tissues. Accumulation of senescent cells accelerates age-related physiological decline and associated pathologies. Furthermore, cellular senescence is implicated in various physiological processes, including embryonic development, wound healing, tumor progression, and immune response regulation. The complexity of the aging process arises from its diverse underlying mechanisms, potential reversibility, and intrinsic heterogeneity. Experimental gerontology focuses on identifying pathogenic modulators that regulate the formation and accumulation of senescent cells, as well as investigating their impact on tissue function. Within the field of experimental gerontology, considerable attention is devoted to identifying pathogenic modulators that regulate the formation and accumulation of senescent cells, as well as to investigating their impact on tissue function. Of particular interest is the characterization of novel molecular mechanisms that govern cellular aging. Key pathogenic molecular pathways include the p53-dependent senescence pathway, the p16INK4a/pRb pathway, and non-canonical pathways like IFIH1-MAVS, which contribute to oxidative stress, DNA damage, activation of SASP, and other cellular dysfunction. This study critically examines how viral and bacterial agents induce cellular senescence, particularly in vitro, reviewing the regulatory mechanisms involved. It discusses genetic variants affecting infection susceptibility and categorizes senescence markers. Investigating the molecular mechanisms underlying cellular aging presents promising avenues for the development of targeted and effective therapeutic interventions. Such strategies may include the selective induction of senescence in cancer cells, suppression of senescence to mitigate age-related diseases, or the comprehensive modulation of aging processes to optimize clinical outcomes.

Post-cardiac arrest myocardial dysfunction (PAMD) is a major contributor to early death (within 72 hours) following return of spontaneous circulation (ROSC). Levosimendan, a calcium-sensitizing inotrope with vasodilatory and mitochondrial-protective properties, offers a potential therapeutic strategy by increasing cardiac output, improving organ perfusion, and attenuating mitochondrial ischemia-reperfusion injury. While experimental evidence suggests multi-organ benefits in cardiac arrest (CA), robust clinical data are lacking.

Gastrointestinal mucormycosis is a rare, life-threatening invasive fungal infection that is often diagnosed late because of nonspecific clinical and endoscopic findings. Khat or Qat (Catha edulis) leaves may harbor environmental fungi, including Mucor species, and chronic chewing may contribute to gastrointestinal mucosal injury. However, a possible association between Qat use and gastrointestinal mucormycosis has not been established. We report a case of a 60-year-old man with diet-controlled type 2 diabetes mellitus and long-standing Qat chewing who was admitted after an out-of-hospital cardiac arrest secondary to acute myocardial infarction. He had no history of malignancy, transplantation, neutropenia, or immunosuppressive therapy. Return of spontaneous circulation was achieved after 34 min of cardiopulmonary resuscitation, followed by temporary venoarterial extracorporeal membrane oxygenation. On hospital day 14, coffee-ground material was observed through the nasogastric tube, accompanied by a decline in hemoglobin from 14.0 to 9.5 g/dL. Esophagogastroduodenoscopy revealed a fungating, ulcerated lesion involving the gastric fundus and body. Histopathological examination demonstrated extensive necrosis, angioinvasion, and broad, ribbon-like, pauci-septate fungal hyphae with irregular branching, consistent with gastric mucormycosis. Intravenous liposomal amphotericin B was initiated at 8 mg/kg/day. Gastrointestinal bleeding resolved without surgery. Repeat endoscopy one month later showed marked healing, and follow-up biopsy revealed no residual fungal elements. The patient completed six weeks of antifungal therapy and achieved clinical and histopathological resolution. Fungal culture and molecular identification were not performed, precluding species-level confirmation.‏ In conclusion, this case describes gastric mucormycosis in a patient without profound immunosuppression but with severe physiological stress and chronic Qat exposure. Critical illness, gastric hypoperfusion, and mucosal disruption may have facilitated fungal invasion. Qat chewing is presented as a hypothesis-generating factor because of possible fungal contamination of leaves and repeated mucosal injury; nevertheless, causality cannot be inferred from a single case. Further microbiological and epidemiological studies are required to investigate this potential association.