Acute liver injury caused by drug toxicity or immune activation remains a major clinical challenge with limited mechanistic understanding and few effective therapies. Here, we identify a previously unrecognized form of regulated cell death driven by palmitoylation of the endoplasmic reticulum (ER)-resident enzyme trans-2,3-enoyl-coenzyme A (CoA) reductase (TECR). We show that multi-site palmitoylation of TECR, redundantly catalyzed by the palmitoyl acyltransferases ZDHHC5 and ZDHHC2 and dynamically reversed by the depalmitoylase ABHD10, activates PERK-dependent ER stress signaling to trigger cell death. This cell death pathway is a TECR-dependent, palmitoylation-induced, ER stress-mediated necrotic cell death program (TPNCD). TPNCD contributes to liver injury in mouse models of acetaminophen- and concanavalin A-induced hepatotoxicity and is attenuated by hepatocyte-specific TECR ablation or by pharmacological inhibition of palmitoylation or ER stress signaling. Together, these findings establish TPNCD as a distinct, necrotic cell death pathway underlying acute liver injury and highlight new therapeutic entry points for hepatoprotection.

Iliac bone grafting is used for autologous reconstruction of bone defects. Donor site pain can be greater than any morbidity related to iliac crest bone graft harvesting, and it is a significant factor in delaying early recovery and rehabilitation. Single-shot or postoperative continuous infusion of local anesthetics through catheters has been described in the literature. We aimed to demonstrate the effectiveness of "postoperative periodic delivery of bupivacaine through a catheter at iliac bone graft donor site" in reducing postoperative pain and facilitating patient mobilization. Seventy-one patients who underwent alveolar bone grafting using iliac crest bone graft were evaluated. These patients were divided into 2 groups, including 36 in the catheter group and 35 in the control group. Patients in the catheter group received 0.3 mg/kg bupivacaine, diluted 1:1 with normal saline through the catheter, administered 4 times daily during the first 36 hours. All patients received standardized systemic analgesia consisting of intravenous paracetamol at a dose of 15 mg/kg every 8 hours and, if additional analgesia was required, intravenous tramadol at a dose of 1 mg/kg. Postoperative pain was assessed using the Burford Pain Thermometer, and all patients were followed for mobilization and complications related to local anesthetic toxicity, the catheter, and the donor site. Patients from the catheter group reported relatively lower levels of postoperative pain as compared with participants in the control group. The total postoperative intravenous tramadol requirement was significantly lower in the catheter group. Moreover, time to first postoperative mobilization was significantly shorter in the catheter group. Periodic catheter delivery of bupivacaine seems to be an effective, safe, easy-to-apply, and well-tolerated technique.

Medication taken for other reasons than for the treatment of malignant disease, termed concomitant medication, is known to affect outcomes when used with immune checkpoint inhibitor therapy and other oncological drugs. However, no research in humans has addressed the relationship between concomitant medications and efficacy of oncolytic adenovirus (OAd) therapy. We retrospectively collected medication history of 290 patients enrolled in the Advanced Therapy Access Program (ATAP), an individualized treatment program of OAds. We analyzed associations of different concomitant medications with overall survival and imaging response following therapy. Additionally, to provide further insights into mechanisms using tissue samples, we collected concomitant medication data, tumor transcriptomic data and serum proteomic data from recent Phase I clinical trials with OAd igrelimogene litadenorepvec (Ad5/3-E2F-d24-hTNF-IRES-hIL2, TILT-123). In ATAP, acetaminophen (paracetamol), opium alkaloids, anti-emetics, proton pump inhibitors, beta blockers, laxatives, and antidepressants use showed a statistical association with shorter overall survival. Use of lipid-modifying drugs (statins) and thyroid hormones showed a statistical association with better disease control in imaging. In clinical trials with TILT-123, beta blockers, anti-emetics, opioids, and benzodiazepines showed a statistical association with shorter overall survival, and lipid-modifying drugs and thyroid hormones showed a statistical association with improved disease control. Tumor transcriptomic and serum proteomic analysis showed varied temporal and locational effects on inflammatory response varying by drug class. The results provide the first human data suggesting that OAd therapy outcomes might be influenced by concomitant medications. Future studies on mechanisms of reported findings have the possibility of tailoring clinical use of OAds.

Biodegradable polymer implants offer long-acting drug delivery, yet the roles of polymer chemistry and drug properties in governing release remain incompletely understood. We hypothesized that polymer viscosity and end-group chemistry regulate water uptake, glass-transition, and chain mobility, thereby controlling implant dissolution and drug release. To test this, drug-loaded implants were fabricated using PLGA and PLA polymers with varied inherent viscosities, lactide/glycolide ratios, and end-group chemistries via vacuum compression molding, and characterized using water-uptake studies, dissolution testing, and NMR analyses. Low-viscosity, acid-terminated polymers showed rapid water uptake and a marked reduction in glass-transition temperature, inducing a transition to a rubbery state with enhanced chain mobility. These changes accelerated implant dissolution and drug release. Drug solubility further modulated drug release: acetaminophen promoted fast dissolution, whereas dexamethasone exhibited slower, polymer-controlled release. The formulations demonstrated a clear in vitro-in vivo relationship, supporting their relevance for preclinical evaluation. Overall, the results establish how polymer chemistry, polymer mobility, and drug physicochemical properties collectively determine release performance, providing a mechanistic basis for designing biodegradable implants with tunable profiles.

Granulocyte colony-stimulating factor (G-CSF) is widely used for stem cell mobilization but is associated with side effects such as pain, which often discourages healthy donors. Jing Si Herbal Tea (JSHT), a novel Chinese herbal formula comprising eight different Chinese herbal medicines, has been shown to exert pleiotropic effects against several disorders. The present study primarily explored the potential effects of JSHT aqueous extract on G-CSF-induced stem cell mobilization and the alleviation of G-CSF-induced pain. The effects of JSHT on G-CSF-induced hematopoietic stem and progenitor cell (HSPC) mobilization and pain-related responses in mice were comprehensively evaluated using flow cytometric analysis, nociceptive behavioral assessments, and immunofluorescence staining. Animal studies demonstrated that JSHT had no significant effect on white blood cell (WBC) levels or HSPC mobilization. However, it helped replenish the HSPC level in the bone marrow following G-CSF-induced mobilization of these cells into the peripheral circulation. Furthermore, JSHT increased IFNγ expression in CD45[+] and CD45[+]CD34[+] cells, suggesting its potential to enhance HSPC activity. JSHT also alleviated thermal hyperalgesia, with effects comparable to those of acetaminophen (APAP), by reducing neuroinflammation and modulating the expression of cannabinoid receptor 1 (CB1) and the sodium channel Nav1.8 in the dorsal root ganglia (DRG), thereby reducing G-CSF-induced pain. JSHT had no effect on HSPC mobilization into the peripheral blood but might help regulate HSPC level within the bone marrow and potentially enhance HSPC function during G-CSF treatment. Additionally, JSHT effectively attenuated G-CSF-induced pain, suggesting its potential as a supportive therapy during G-CSF-induced stem cell mobilization.

Van Neck-Odelberg disease is a benign disorder of the ischiopubic synchondrosis (IPS) that can be mistaken for infection, fracture, or bone tumor. A boy aged 10 years and 7 months presented with a 1-year history of exertional groin pain and intermittent limping. The pain was bilateral but consistently worse on the right and was aggravated by football and running. He was afebrile. Examination showed a mild right antalgic gait, focal tenderness over the right ischiopubic region, and pain on combined right hip flexion and external rotation. The white-cell count (4.9 × 10[9]/L) and erythrocyte sedimentation rate (2 mm/h) were within the reference ranges. A C-reactive protein result was unavailable. Pelvic radiography showed smooth, asymmetric enlargement and central lucency of the right IPS without an aggressive periosteal reaction. MRI confirmed widening of the synchondrosis with surrounding marrow edema. The cortex remained intact, and there was no abscess or soft-tissue mass. A transverse hypointense band perpendicular to the pubic axis represented the characteristic fibrous bridge. The clinical and imaging findings supported a diagnosis of symptomatic Van Neck-Odelberg disease, and biopsy was avoided. Management consisted of acetaminophen as required, activity restriction for 2 weeks, and once-weekly physiotherapy for 6 months with hip adductor and external rotator stretching. Initial improvement in pain and limping occurred at 4-6 weeks, with complete clinical recovery at 6 months. The combination of a 1-year symptom history, bilateral pain with unilateral imaging findings, and a preserved fibrous bridge illustrates how recognition of the typical imaging appearance, together with the clinical and laboratory findings, can prevent unnecessary antibiotics, biopsy, and oncological investigation.

Acetaminophen (N-acetyl-p-aminophenol, APAP) is a widely used pharmaceutical and an emerging micropollutant of ecological concern in aquatic environments. However, the taxonomic diversity of APAP-degrading bacteria remains poorly understood. An APAP-degrading strain, Labrys sp. XQ-1, was obtained from municipal wastewater and was capable of utilizing APAP as the sole added carbon and energy source for growth. Removal of 99% of 100 mg/L APAP was achieved within 36 h under optimal conditions (30 °C, pH 7.0, 1% NaCl). Kinetic analysis indicated that APAP degradation by strain XQ-1 was best described by a first-order model (R[2] = 0.988). Genome sequencing further identified a hydrolase-encoding gene, apbH, classified within the Amidase Signature (AS) superfamily. Functional assays confirmed that ApbH could catalyze the initial deacetylation of APAP to 4-aminophenol. Enzyme kinetics, molecular docking analysis, and site-directed mutagenesis supported the functional importance of Lys135, Ser210, and Ser234 in ApbH-mediated APAP transformation. Batch reactor experiments further confirmed efficient APAP removal in both mineral salt medium and simulated wastewater, with transient accumulation and subsequent disappearance of 4-AP. These findings expand the known diversity of APAP-degrading bacteria and provide new insights into its biodegradation.