Browse Articles

HIF-2α induction in de novo lipogenesis in metabolic dysfunction-associated steatohepatitis is dependent on IL-21 signaling

Preoperative muscle quantity to predict acute kidney injury after radical cystectomy: A multicenter retrospective study.

723 Background: Acute kidney injury (AKI) is a common complication in patients undergoing radical cystectomy (RC), yet its risk factors remain poorly defined. AKI is diagnosed based on elevations in serum creatinine levels, which are primarily influenced by skeletal muscle mass—the main source of creatinine production. Therefore, we hypothesized that preoperative muscle quantity and quality may play a critical role in the development of AKI following RC. Methods: This multicenter retrospective cohort study included 918 patients with bladder cancer who underwent RC. AKI was defined according to the KDIGO criteria. Muscle quantity and quality were assessed using the psoas index (PI) and intramuscular adipose tissue content (IMAC), respectively, based on computed tomography images obtained within one month prior to RC. Optimal cutoff values for predicting AKI were determined separately for men and women using receiver operating characteristic curve analysis. A higher PI and lower IMAC reflect greater muscle quantity and quality, respectively. Multivariable logistic regression analyses were conducted to evaluate the association between muscle metrics and AKI risk. Results: The median age was 70 years. Of the 918 patients, 479 (52%) developed AKI of any stage. Among them, 540 (59%) had higher PI values and 641 (70%) had lower IMAC values. IMAC values were not significantly correlated with PI values (ρ = 0.021, P = 0.530). The incidence of AKI was significantly higher in patients with higher PI values (indicative of greater muscle quantity) than in those with lower PI values (56% vs. 47%, P = 0.007). Conversely, patients with lower IMAC values (indicative of better muscle quality) had a significantly lower incidence of AKI compared to those with higher IMAC values (50% vs. 57%, P = 0.037). After adjustment for confounding variables, higher muscle quantity (higher PI values) was significantly associated with AKI development ( P = 0.003; odds ratio [OR]: 1.590; 95% confidence interval [CI]: 1.166–2.168), whereas muscle quality (lower IMAC values) was not ( P = 0.904; OR: 0.979; 95% CI: 0.698–1.375). Conclusions: Patients with greater muscle quantity were at increased risk of AKI following RC. In contrast, muscle quality did not significantly influence AKI development. Multivariable analysis for AKI development. Factor P value Odds ratio 95% CI Age Continuous 0.124 1.014 0.996–1.033 Sex Male 0.002 1.747 1.236–2.470 Performance status Continuous 0.055 1.398 0.992–1.971 Body mass index Continuous 0.055 1.045 0.999–1.093 Hypertension Presence 0.003 1.556 1.158–2.089 Preoperative eGFR Continuous <0.001 0.984 0.976–0.992 Higher muscle quantity Presence 0.003 1.590 1.166–2.168

CT- vs 1.5T MR-guidance in salvage radiotherapy of locally recurrent prostate cancer after radical prostatectomy.

368 Background: This study compares the treatment outcomes of megavoltage CT-guided RT (CTgRT) and 1.5T MR-guided RT (MRgRT) in prostate cancer patients with gross local recurrence after radical prostatectomy. Methods: We reviewed patients who received salvage RT for locally recurrent prostate cancer between January 2009 and August 2024. All patients had a gross recurrence in the prostate bed, detected via diagnostic MRI and elevated prostate-specific antigen (PSA). Patients in the CTgRT group received conventionally fractionated (28–30 fractions) salvage RT with simultaneous integrated boost. A typical dose scheme is 2.5 Gy to the gross recurrence, 2.25 Gy to the prostate bed, 2.15 Gy to intermediate-risk planning target volume (PTV) with a 5-mm margin, and 1.8 Gy to low-risk PTV with additional 5-mm margin, delivered over 28 fractions. With the introduction of MRgRT in August 2021, patients received moderately hypofractionated RT (2.4 Gy x 24 fractions) to a PTV defined by 4-mm margin added to the prostate bed followed by cone down MRI/CT simulation and sequential boost (2.4 Gy x 3 fractions) to gross recurrence. Acute and late toxicities were evaluated using CTCAE 5.0. Results: A total of 38 patients, 20 in CTgRT and 18 in MRgRT groups, were included. The median recurrence interval and follow-up after radical prostatectomy were 44.0 and 28.5 months and 128.0 and 56.4 months for CTgRT and MRgRT, respectively. The median volume of the gross recurrence was 1.38 cc (range, 0.34–42.66 cc) and 1.30 cc (range, 0.16–27.89 cc) for CTgRT and MRgRT, respectively. Thirteen patients in CTgRT and 16 in MRgRT groups received a boost to the gross recurrence. The median total equivalent dose in 2-Gy fractions was 77.44 Gy (range, 64.18–85.71 Gy) for CTgRT and 72.21 Gy (range, 64.18–83.35 Gy) for MRgRT. Androgen deprivation therapy was administered at recurrence for 11 and 13 patients in CTgRT and MRgRT groups, respectively. Median prostate-specific antigen levels decreased from 0.4 ng/mL pre-RT to 0.11 ng/mL at three months post-RT in the CTgRT group, and from 0.31 ng/mL to 0.04 ng/mL in the MRgRT group. In the CTgRT group, 14 patients had imaging follow-up showing complete response (CR) in 11 patients. In the MRgRT group, 8 patients had imaging follow-up showing CR in 6 patients. No local failure was reported. No grade 3 or higher acute gastrointestinal or genitourinary toxicity was reported in either group. For late toxicity, grade 1 or 2 GU toxicities were reported in nine patients in the CTgRT group, while one patient experienced grade 3 GU toxicity. In the MRgRT group, one patient experienced grade 1 late GI toxicity, and four patients had grade 1 or 2 GU toxicities. Conclusions: MR-guided salvage RT for grossly recurrence prostate cancer allowed reduced target margin and total dose compared with CT-guided salvage RT, resulting in similar RT response and improved toxicity profile.

A provocative analysis of first-line strategies in advanced urothelial carcinoma: Reconstructed individual patient data comparisons of EV–pembrolizumab, avelumab maintenance, and nivolumab–cisplatin–gemcitabine from their pivotal phase 3 trials.

751 Background: The treatment of advanced urothelial carcinoma has been revolutionized by immune checkpoint inhibitors and antibody–drug conjugates, notably enfortumab vedotin (EV). Phase III trials established the efficacy of EV plus pembrolizumab (P), avelumab maintenance and nivolumab combined with cisplatin–gemcitabine (Nivo-CG). However, direct comparisons among these strategies are lacking. Methods: Individual patient data (IPD) were reconstructed from published Kaplan–Meier curves of JAVELIN Bladder 100, EV-302, and CheckMate 901. Reconstruction quality was assessed with stringent, preplanned criteria to ensure high concordance with original survival data. To emulate the JAVELIN design, analyses involving avelumab applied a 5-month landmark approximating completion of platinum induction, excluding early events. Comparative analyses included Cox regression, piecewise HRs, Royston–Parmar models for time-varying hazard ratios [HR(t)], and restricted mean survival time (ΔRMST). Results: Reconstructed curves closely matched published outcomes. EV–P conferred a strong progression-free survival (PFS) advantage over avelumab maintenance (HR 0.55, 95% CI 0.45–0.67, p<0.001; ΔRMST +4.8 mo at 24 mo, p<0.001). For overall survival (OS), EV–P vs avelumab showed early HR(t) benefit at 6 mo (HR 0.67, 95% CI 0.47–0.96, p=0.03) but minimal ΔRMST difference (<1 mo at 24 mo). In cisplatin-eligible patients, EV–P showed clear OS superiority over Nivo–CG (HR 0.59, 95% CI 0.44–0.78, p<0.001; ΔRMST +3.0 mo at 28 mo). By contrast, avelumab maintenance vs Nivo–CG showed early OS differences favoring avelumab, likely reflecting patients who had progressed but remained alive at the 5-mo landmark. HR(t) approached 1 beyond 12 mo and remained stable thereafter, while ΔRMST indicated modest but consistent survival gains for avelumab (+1 to +2 mo at 12–24 mo). Conclusions: This exploratory and hypothesis generating reconstructed-IPD analysis demonstrates the clear OS superiority of EV–P over concomitant chemo-immunotherapy and its robust PFS advantage versus maintenance immunotherapy. However, the OS gain over sequential platinum–avelumab is modest, suggesting comparable long-term clinical outcomes in selected patients. Notably, avelumab maintenance achieved OS comparable to Nivo–CG indicating that maintenance immunotherapy may offer similar benefit without upfront chemo-immunotherapy.

Coupling Pt Single‐Atoms with Amorphous LDH Nanosheets as a High‐Efficiency Sonosensitizer for Sonodynamic Immunotherapy

ABSTRACT Sonodynamic therapy (SDT) represents a minimally invasive alternative for cancer treatment. However, its efficacy is constrained by the insufficient reactive oxygen species generation of inorganic sonosensitizers due to wide bandgaps, rapid electron‐hole recombination, and insufficient oxygen adsorption/activation. Herein, we report for the first time a novel sonosensitizer constructed by anchoring Pt single‐atoms onto amorphous CoMgMo‐layered double hydroxide (Pt/a‐LDH) for high‐efficiency sonodynamic immunotherapy. Through the synergy of defect engineering and single‐atom modification, Pt/a‐LDH achieves sharp bandgap reduction (from 2.4 to 0.6 eV) and abundant defective environment, dramatically promoting charge separation and inhibiting electron‐hole recombination (an inhibition rate of 89.8%). Moreover, the unique 2D structure and hydroxyl coordination environment of LDH yield ultrahigh single‐atom loading efficiency and defect density, which significantly promote oxygen adsorption/activation, reduce reaction energy barrier (bond energy from 3.6 to 2.1 eV), and accelerate reaction kinetics. Consequently, Pt/a‐LDH achieves a significant enhancement in sonodynamic performance, generating singlet oxygen at 5.3 and 38.2 times that of CoMgMo‐LDH and TiO 2 sonosensitizer, respectively. In vivo assays demonstrate that polyethylene glycol‐modified Pt/a‐LDH induces robust immunogenic cell death, activates dendritic cell maturation, stimulates T‐cell infiltration, and reprograms the immunosuppressive tumor microenvironment, offering a new paradigm for high‐performance sonodynamic immunotherapy.

Effective Manipulation of Skyrmions via Strain Gradient

ABSTRACT Skyrmion‐based devices hold considerable potential for memory, logic, and sensing applications, where precise control over skyrmion density and size is essential. While strain engineering offers an energy‐efficient route to tune these properties, excessive strain can induce plastic deformation in magnetic films or lead to cracking, compromising the reliability of strain‐mediated skyrmion control. Here, we demonstrate strain gradients as an effective additional control parameter in magnetic multilayers. By introducing microscale periodic wrinkled structures in sputtered Pt/Co/Ta multilayers, strain gradients with varying magnitudes and directions are generated. Magnetic force microscopy reveals that both skyrmion density and size vary synchronously with the in‐plane strain gradient, enabling broader tunability than uniform strain approaches. Micromagnetic simulations confirm that these effects arise from strain and strain gradient modulation of the Dzyaloshinskii‐Moriya interaction and magnetic anisotropy. Moreover, this control strategy is reversible, cyclable, and transferable across different magnetic multilayers, providing a practical avenue for precise skyrmion engineering. This approach offers significant promise for advancing flexible spintronics, skyrmion‐based memory, and neuromorphic computing architectures.

An evolutionarily conserved salt bridge stabilizes the active site for GTP hydrolysis in Rho GTPases

Aligning goals of care at the time of treatment planning with the ABC123 framework: A pilot study.

726 Background: Older patients with incurable genitourinary (GU) cancers are at high risk for receiving care that does not align with their goals. This study assessed the feasibility and acceptability of a treatment planning framework including validated geriatric, oncologic, and palliative approaches at initial assessment to better align and improve care. Methods: This single-arm pilot study evaluated the feasibility and acceptability of the ABC123 framework for aligning cancer treatment with older adults’ goals. Originally designed for an advanced bladder cancer (ABC) population, the framework integrates 1. geriatrics (geriatric functional assessment), 2. oncology (chemotherapy toxicity), and 3. palliative care (goals-of-care discussions) delivered by an advanced practice provider. The intervention occurred within 2 weeks of the initial oncology visit and patients followed up (FU) at 1, 3, and 6 months. We enrolled patients aged ≥ 65. The primary outcome was feasibility (recruitment and retention). Secondary outcomes included patient-oncologist care alignment, acceptability, goal-concordant care (Ottawa Decision Scales and Advanced Illness Coordinating Care Survey [AICCS]), and quality of life. Results: The study was feasible with 50% of those approached consented (n = 34). Although expected attrition occurred, 16 completed the 1 mo FU and 12 completed 3 mo FU measures. The study expanded beyond bladder cancer and 9 patients had a GU cancer. At 1 mo FU, 75% patient-oncologist goals of treatment were most aligned, with 17% less aligned, and 8% least aligned (Table 1). At baseline, the mean AICCS score was 3.8, increasing to 4.4 at 3 mo (p = 0.02). No significant differences were observed for Ottawa Self-Efficacy (89.9 vs. 88.1, p = 0.49), Decision Conflict (26.7 vs. 19.6, p = 0.25), Informed subscale (29.0 vs. 23.1, p = 0.44), Value Clarity subscale (27.2 vs. 19.9, p = 0.42), or FACT-G (2.8 vs. 3.0, p = 0.89). Items were coded so a more positive outcome is indicated by a higher score except Decisional Conflict and its subscales. No differences in demographics or cancer/co-morbidities were noted between those who completed 3 mo outcomes and those who did not. Conclusions: This pilot study demonstrated the feasibility of enrollment and follow-up in older patients with incurable cancer, with staff and patients noting acceptability of the design including delivery of a primary goals of care discussion by an advanced practice provider. Excellent patient-oncologist care alignment was noted, and most patient-reported outcomes trended to improvement. A larger randomized study was planned based on this pilot experience. Goal of treatment assignment. 1-Month Oncologist Perspective PatientPerspective Supportive Life prolonging Rehabilitative Curative Supportive 0 2* 0 0 Life prolonging 0 9** 0 0 Rehabilitative 0 0 0 0 Curative 1# 0 0 0 Most aligned=**; Less aligned=*; Least aligned=#.

A multicohort phase 2 trial of androgen deprivation therapy (ADT), docetaxel (DOCE), and nivolumab (NIVO) in patients (pts) with newly diagnosed metastatic hormone sensitive prostate cancer (mHSPC) enriched for inflamed tumors and DNA damage repair (DDR) alterations.

183 Background: This multicenter phase 2 investigator-initiated trial evaluated ADT, DOCE, and NIVO in pts with de novo mHSPC. Cohorts were prospectively allocated by the presence of DDR alterations (C1), PD-L1 and CD8 positivity (C2), or absence of biomarkers (C3). Primary results from all cohorts are reported. Methods: Pts with newly diagnosed mHSPC (ECOG 0-2 and PSA >4.0ng/mL before ADT) were enrolled, allowing up to 140 days of prior ADT. Pts received continuous ADT, DOCE 75mg/m 2 and NIVO 360mg Q3W for 6 cycles, followed by NIVO 480mg Q4W for up to 2 years. Primary endpoint (PEP) was PSA < 0.2ng/mL at 7mo and considered promising if 2-sided 80% CI exceeded 20%. Secondary endpoints included PSA < 0.2ng/mL before next therapy, objective response rate (ORR), time to castration resistance (TTCRPC), overall survival (OS) and adverse events (AE). Planned enrollment was 60 pts (20/cohort). Biomarkers were centrally assessed. Results: 47 pts were enrolled between 5/2020-3/2024 (C1: 8, C2: 19, C3: 20). Due to evolving treatment landscape, abiraterone was permitted post-7mo in 1/2022, and enrollment was subsequently stopped early. Across cohorts, median age was 65y (IQR 60-72) and median PSA at ADT start 98ng/mL (IQR 36-477). 41 (87%) pts had high-volume metastases with 11 (23%) visceral disease. Median follow-up was 42mo. Pts received a median of 6 DOCE and 11 NIVO cycles. PSA < 0.2ng/mL at 7mo occurred in 3 (38%, 80% CI: 15%-66%) pts in C1, 3 (16%, 5.9%-32%) pts in C2, and 3 pts (15%, 5.6%-30%) in C3; 6 pts (2 in C2, 4 in C3) lacked data due to early discontinuation for AE or physician decision. Rate of PSA < 0.2ng/mL before next therapy was 4 (50%) in C1, 4 (21%) in C2, and 4 (20%) in C3. ORR was 0% (0/2) in C1, 50% (4/8) in C2, and 50% (6/12) in C3. Abiraterone was started by 11 (23%) pts on study, with median time from C1D1 of 11mo (range: 7-19). Survival outcomes are summarized in Table. Grade 3-4 treatment-related AEs occurred in 28 (60%) pts, most frequently neutropenia (30%) and leukopenia (11%). Conclusions: C2 and C3 did not meet the 7mo PSA response PEP, and C1 was underpowered for assessment. Pts with PD-L1 and/or CD8 high tumors tended to have longer TTCRPC and OS; however, the study was not designed for cross-cohort comparisons. Safety was consistent with individual profiles of each agent. With the expanding therapeutic arsenal for mHSPC, future studies should further explore biomarker-driven combination strategies to optimize treatment selection and pt outcomes. (NCT04126070). Clinical trial information: NCT04126070 . Cohort 1 (DDR altered, N=8) Cohort 2 (PD-L1/CD8 high, N=19) Cohort 3 (Biomarker negative, N=20) TTCRPC, median (95% CI) 8.8 (6.2-NR) 14.3 (5.3-38.6) 7.9 (5.1-NR) 3yr OS rate, % (95% CI)* 55 (14-83) 72 (46-87) 59 (33-78) *Median OS not reached in each cohort.

Integrating circulating tumor DNA (ctDNA) and <i>TP53</i> alteration variant allele frequency (VAF) to predict outcomes in advanced urothelial carcinoma (aUC) treated with enfortumab vedotin (EV).

815 Background: EV, alone or combined with pembrolizumab (EVP), is a standard of care for patients (pts) with aUC. Markers predictive of early or durable treatment response in aUC remain limited. Here, we investigate serial ctDNA monitoring and TP53 VAF as complementary predictors of early EV/EVP response. Methods: This single-institution IRB-approved study included pts with aUC treated with EV/EVP between 1/2021 and 9/2025. Pt demographics, clinicopathologic features, serial Signatera ctDNA results, and somatic tissue next-generation sequencing (NGS) data were abstracted from medical records. Primary refractory disease (PRD) was defined as progressive disease on first restaging scan or earlier clinical progression resulting in death from disease. PRD and progression-free survival (PFS) were assessed using Fisher’s exact and log-rank tests. Results: Out of 158 pts, 67 pts were included in study cohort. Median follow-up was 13.2 months, with 52% of pts alive at time of data cutoff. Clinical characteristics at EV start include median age 69 years (range 41-99), 78% male, 91% white, 15% variant-predominant histologic subtype, 15% upper tract disease, 43% with visceral metastasis (24 lung, 7 liver), 66% frontline treatment (42 EVP, 2 EV), and 34% refractory setting (6 EVP, 17 EV). At first restaging scan, observed response rate was 50%; 23% had PRD. TP53 alterations on NGS were identified in 39 pts (58%); TP53 VAF was available for 36 pts (92%), with median VAF 50.7% (range 8-82%). While TP53 mutation presence did not significantly associate with PFS (hazard ratio [HR] 1.28, 95% CI 0.68-2.42; log-rank p = 0.45), pts with TP53 VAF ≥ 50% had significantly longer PFS compared with TP53 VAF &lt; 50% (HR 0.44, 95% CI 0.18-1.04; log-rank p = 0.03). PRD was more commonly observed with TP53 VAF &lt; 50% than with TP53 VAF ≥ 50% (odds ratio [OR] 0.06, 95% CI 0.01-0.48, p = 0.01). 23 pts (21 EVP, 2 EV) had ≥ 2 serial ctDNA draws ≤ 120 days apart, including baseline draw within 2 months of EV start. Median time between 1 st and 2 nd ctDNA draws was 43 days. 70% (16 pts) had ≥ 90% ctDNA decline and 17% (4 pts) had ctDNA rise. The 2 pts with PRD exhibited ctDNA rise, whereas no pts with ctDNA decline had PRD (p = 0.04). 10 of these pts (43%) had TP53 mutations with available VAF. Of those 5 pts with TP53 VAF ≥ 50%, 3 had ctDNA clearance over 90%, 1 had 0-90% ctDNA clearance, and 1 had ctDNA rise. Of those 5 pts with TP53 VAF &lt; 50%, 2 had ctDNA clearance over 90%, 1 had 0-90% ctDNA clearance, and 2 had ctDNA rise. Conclusions: Integrated serial ctDNA monitoring and tumor TP53 VAF may capture early treatment sensitivity to EV/EVP. Limitations include retrospective analysis, small sample size/power, combined EV/EVP cohort, and lack of centralized imaging review. Further validation in large, prospective cohorts is warranted.

Bioinspired Engineered Virus‐Mimetic Vesicles for Enhanced Cytosolic Delivery of STING Agonists Into Dendritic Cells

ABSTRACT Effective delivery to dendritic cells (DCs) is crucial for the clinical translation of STING agonists, however, current cyclic dinucleotide (CDN) therapies are hindered by inefficient cytosolic delivery and off‐target activation‐induced T cell exhaustion. Here, a high‐fidelity, dengue virus‐mimetic platform (CDN@VLP) is engineered to leverage natural tropism for precise cytosolic release in immature DCs. Compared to conventional lipid nanoparticles, CDN@VLP enhances DC‐specific uptake by 1.9‐fold while reducing non‐specific T cell internalization in tumors by 14.8‐fold, achieving comparable antitumor efficacy at one‐fortieth the dose of free CDN. Systematic screening identifies an optimal VLP subtype that improves targeted accumulation in type 1 conventional DCs (cDC1s)—a subset essential for STING pathway activation—by 2.3‐fold and amplifies durable type I interferon responses, resulting in a 12.8‐fold increase in IFN‐β production. Transcriptomic analysis further reveals that CDN@VLP promotes cDC1 recruitment into tumors by enhancing the secretion of key chemokines (XCL1, CCL4, and CCL5), suggesting an additional mechanism of action. By mimicking viral tropism, the CDN@VLP platform establishes a paradigm for precision STING activation, overcoming the trade‐off between potency and specificity in cDC1‐targeted immunotherapy.

Non‐Destructive Laser Nanopatterning of Superconducting Heterostructures in Topological Sn Thin Films

ABSTRACT Heterostructures composed of superconductors and topological materials have emerged as compelling platforms for realizing topological superconductivity and fault‐tolerant quantum computation. A critical bottleneck, however, lies in achieving atomically clean and structurally coherent interfaces between dissimilar materials. Here, we report the fabrication of high‐quality planar heterostructures composed of the topological Dirac semimetal (TDS) α‐Sn and the superconducting β‐Sn phase, achieved by focused laser irradiation on α‐Sn thin films. The irradiated regions undergo a phase transition from α‐Sn to β‐Sn, exhibiting atomically smooth surfaces with a root mean square (RMS) roughness of just 0.75 nm. The laser‐induced β‐Sn demonstrates superconductivity with a critical temperature of 3.7 K and a Ginzburg–Landau coherence length ( ξ GL ) of 68.2 nm. Notably, β‐Sn nanowires patterned through this method exhibit a pronounced superconducting diode effect, reaching a maximum rectification ratio ( η ) of 10.8%. These findings establish laser irradiation as a versatile, non‐destructive, and scalable approach for fabricating high‐quality α‐Sn/β‐Sn heterostructures, offering a promising route toward next‐generation superconducting quantum devices.

Hypoxia-inducible factor 1αa regulates lipid metabolism to coordinate adipocyte hypertrophy and hyperplasia in grass carp

Effect of tumor methionine metabolism via MAT2A on CD8⁺ T-cell exhaustion through SAM-CHOP axis in bladder cancer.

811 Background: Bladder cancer shows high recurrence and limited benefit from immune-checkpoint blockade. Tumor metabolic reprogramming reshapes nutrient availability, thereby constraining T-cell function. Methionine metabolism, which generates the universal methyl donor S-adenosylmethionine (SAM), supports both tumor growth and T-cell epigenetic activity. The enzyme methionine adenosyltransferase 2A (MAT2A) catalyzes this step, but how tumor-intrinsic MAT2A influences antitumor immunity remains unknown. Methods: We integrated multi-omics analyses (RNA-seq, scRNA-seq, ChIP-seq) with CRISPR/Cas9 editing, metabolite quantification, and orthotopic mouse models. Patient cohorts were evaluated by immunohistochemistry and survival analysis. Functional studies combined MAT2A perturbation, SAM supplementation, and cisplatin treatment to examine metabolic competition, ER-stress signaling, and immune-checkpoint regulation in CD8⁺ T cells. Results: MAT2A was markedly upregulated in bladder cancer and independently predicted poor survival (HR = 3.52, p &lt; 0.001). Cisplatin activated NRF2, which bound antioxidant-response elements in the MAT2A promoter and induced transcription. Tumor MAT2A consumed methionine and depleted SAM in the tumor microenvironment (−51% vs plasma), reducing the SAM/SAH ratio in neighboring CD8⁺ T cells and impairing IFN-γ secretion. SAM deficiency triggered PERK–eIF2α–CHOP activation, and CHOP bound PDCD1 and CTLA4 promoters, upregulating immune-checkpoint genes. CHOP deletion or PERK inhibition restored cytokine release. In vitro, SAM promoted tumor proliferation, yet in immunocompetent mice it enhanced CD8⁺ T-cell infiltration and effector activity. Combining SAM with cisplatin reduced tumor volume by 57% and prolonged survival ( p &lt; 0.01). Human specimens confirmed positive correlations among MAT2A, CHOP, and PD-1 expression ( r = 0.72) and poor prognosis in MAT2A^high/CHOP^high tumors. Conclusions: Tumor-intrinsic MAT2A reprograms methionine metabolism to deprive T cells of SAM, activating CHOP-dependent transcription of immune checkpoints and driving exhaustion. Targeting the MAT2A–SAM–CHOP axis or replenishing SAM restores T-cell function and enhances chemotherapy efficacy, revealing a metabolic checkpoint that links nutrient competition to immune escape in bladder cancer.

Proliferation- and immune-informed fusion of multiscale image features for bladder cancer prognosis.

802 Background: Predicting bladder cancer outcomes remains challenging due to pronounced tumor heterogeneity, a challenge that is inadequately addressed by the limited prognostic power of single-modality models. Although mitotic activity and tumor-infiltrating lymphocytes are both established prognostic pathology hallmarks in bladder cancer, their combined value for prognostic modeling has not been previously assessed. Methods: We present HyMiTiM (Hypergraph fusion of Multimodal Image features with Tumor Infiltration and Mitotic activity informed), a multimodal framework that integrates computed tomography (CT) and whole-slide image (WSI) features to predict bladder cancer prognosis. The first branch, HyMi, captures intratumoral heterogeneity by decomposing multiscale inputs into tumor-centered CT subvolumes and WSI patches. A lightweight hypergraph models cross-scale feature interactions between those fine-grained elements, and an attention pooling head aggregates them into a patient-level representation. To enhance biological interpretability, two additional WSI-based branches quantify pathomic phenotypes associated with immune infiltration lymphocytes (TIL) and mitotic activity, anchoring survival prediction in established bladder cancer morphological hallmarks. The final HyMiTiM risk score is derived by applying Platt scaling to the three branch outputs, producing a unified prognostic score. HyMiTiM was trained on the Qingdao Provincial Hospital cohort (QDPH, N = 436) and externally tested on the TCGA cohort (N = 71) and the Zhejiang Provincial Hospital (ZJPH, N = 43) cohort using matched CT scans and WSI. Results: In univariable analysis, HyMiTiM was prognostic of progression-free survival (PFS) on the TCGA cohort (HR = 2.26, 95% CI, 1.08–4.75, p = 0.0272) and ZJPH cohort (HR = 3.82, 95% CI, 1.44–10.17, p = 0.004). In terms of C-indices on the two external test cohorts, HyMiTiM (0.70 and 0.75) outperformed the three individual input branches: HyMi score (0.68 and 0.66), TIL score (0.67 and 0.63) and mitotic activity level (0.61 and 0.62). Conclusions: By unifying deep embeddings across radiology CT and pathology WSI as well as interpretable morphology phenotypes within WSI, HyMiTiM provides an interpretable multimodal fusion framework for bladder cancer prognosis.

Prevalence of treatment-acquired homozygous losses (homozygous deletions) of <i>PTEN</i> from androgen receptor pathway inhibitors (ARPI) in metastatic prostate cancer.

27 Background: Validated homozygous loss detection is becoming increasingly important in clinical practice, with prostate NCCN guideline inclusion of BRCA1/2 loss (often portending durable PARP inhibitor benefit) and multi-tumor trials of PRMT5 and MAT2A inhibitors ongoing (biomarker: MTAP loss). Homozygous losses are challenging to detect and require intentional NGS assay design and validations. Using an FDA-approved NGS assay, we evaluated the most frequent losses identified in metastatic prostate cancer, evaluated prognostic associations on ARPI, and prevalence before and after ARPI treatments. Methods: This study used the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine Prostate Cancer clinico-genomic database (FH-FMI CGDB), originating from approximately 280 US cancer clinics (~800 sites of care). Patients with metastatic prostate cancer and tissue tumor genomic testing by FoundationOne CDx were eligible for analysis. Alteration prevalence was compared between non-sequential groups of specimens obtained from patients naïve to ADT and ARPI, naïve to ARPI but not ADT, or exposed to any ARPI. Outcome analyses adjusted for: ECOG performance score, age, baseline PSA, and socioeconomic status. To limit immortal time confounding, outcome analyses were restricted to patients with specimens tested prior to initiation of ARPI. Results: 1990 specimens from 1984 unique patients met criteria for assessment. The most common losses and respective ADT &amp; ARPI naïve vs ADT exposed &amp; ARPI-naïve vs ARPI-exposed prevalence were PTEN (17.1% vs 24.8% vs. 33.5%, p &lt; 0.001), FAS (2.4% vs 5.0% vs 5.8%, p = 0.003), BRCA2 (4.2% vs 3.2% vs. 2.8%, p = 0.36), RB1 (1.6% vs 3.0% vs 3.5%, p = 0.062), and TP53 (2.3% vs 2.3% vs 4.4%, p = 0.064). 227 patients had tissue specimens obtained and NGS results reported prior to initiation of ARPI. Sufficient patients with PTEN loss were present for nominal outcome associations, observing less favorable time to next treatment (HR: 1.81, 95%CI: 1.24 – 2.65, p = 0.002) and overall survival (HR: 1.65, 95%CI: 1.02 – 2.65, p = 0.040) from the initiation of ARPI. In the mHSPC (ADT and ARPI naïve) setting, 17.1% had PTEN loss, 32.8% had an HRR gene alteration, and 2.8% had both. Conclusions: Our results are consistent with homozygous losses of certain genes, notably PTEN , potentially being acquired resistance alterations to ARPI. Prostate cancer trials often do not specify timing of specimen acquisition relative to treatment initiation. For trials like IPATential-150 or CAPItello-280 that evaluate AKT inhibitors in post-ARPI setting, patients with PTEN status determined by archival tissue could be false negatives and reduce power of analysis in biomarker(+) group. Our results underscore the importance of clinical context, especially prior treatment exposures, when interpreting biomarker prevalence.

Efficient Non‐Invasive Rejuvenation of Spent Lithium Iron Phosphate Batteries Through Controlled Overdischarge

ABSTRACT Recycling lithium iron phosphate (LFP) batteries presents critical economic and environmental challenges because of their low metal value and high energy intensity of conventional metallurgical processes. While direct recycling methods offer a pathway for lithium replenishment, they are often hindered by stringent impurity controls and complex operating conditions that limit scalability. Here, we introduce a controlled overdischarge (COD) protocol as a non‐invasive strategy to rejuvenate spent LFP (S‐LFP) batteries. COD selectively decomposes the solid‐electrolyte interphase, releasing trapped Li + and reducing Li/Fe antisite defects while simultaneously suppressing copper dissolution. The COD protocol recovers 9.56% of lost capacity and extends lifespan by over 200 cycles. Furthermore, compared to metallurgical recycling, this method markedly lowers greenhouse gas emissions to 168 g kg −1 and energy consumption to 3 MJ kg −1 of feedstock. These findings highlight COD as a sustainable and scalable alternative for S‐LFP battery recycling.

Interlayer Coupling in Organic‐Inorganic Heterostructures via Interfacial F···S Interactions for Near‐Infrared Photodetection and Real‐Time Motion Recognition

ABSTRACT Interlayer coupling serves as a powerful strategy for manipulating the optoelectronic characteristics of van der Waals heterostructures. Although the combination of organic and inorganic semiconductors has enabled versatile optoelectronic applications, interlayer coupling in organic–inorganic heterostructures is still limited by inherent material discrepancies such as lattice matching and stacking order. Herein, we demonstrate an interlayer–coupled organic–inorganic heterojunction achieved by interfacial noncovalent F···S interactions, which is composed of molecular 5,5''‐bis(2‐fluorophenyl)‐2,2':5',2''‐terthiophene (oF‐PTTTP) and 2D molybdenum disulfide (MoS 2 ). By leveraging the conformational flexibility afforded by the full C─C single bonds in its backbone, the oF‐PTTTP molecules can self‐adjust their conformations upon thermal activation. The fluorine atoms on the side chains of oF‐PTTTP engage in noncovalent interactions with the sulfur atoms of MoS 2 at the heterointerface, inducing a pronounced interlayer coupling effect accompanied by lattice strain. This coupling enables near‐infrared (NIR) photodetection in a spectral range inaccessible to each individual component, yielding a specific detectivity of 1.8 × 10 14 Jones at 808 nm, which is one of the highest values reported for organic–inorganic heterostructures. Furthermore, the device exhibits gate‐tunable positive and negative photoresponses at 808 nm, allowing real‐time motion imaging in the NIR spectrum.

The KANSL1-ARL17A fusion gene generates oncogenic chKANSARL and F-circKA RNAs that synergistically drive lung cancer progression via a novel F-circKA/miR-6860/chKANSARL axis

Patient reported outcomes (PRO) and tolerability of capivasertib (capi) plus abiraterone (abi) versus placebo (pbo) plus abi in patients (pts) with PTEN-deficient metastatic hormone-sensitive prostate cancer (mHSPC): CAPItello-281.

14 Background: An unmet need for targeted treatments exists for pts with PTEN deficient mHSPC. In the Phase 3 CAPItello-281 study (NCT04493853), capi+abi significantly improved radiographic progression-free survival vs pbo+abi in pts with PTEN deficient de novo mHSPC (HR 0.81 95% CI 0.66, 0.98; P =0.034). Here, we report on PRO and tolerability. Methods: Pts with PTEN deficient tumors (≥90% of viable malignant cells with no specific cytoplasmic staining by immunohistochemistry) received (1:1) capi or pbo with abi + prednisone/prednisolone and androgen deprivation therapy. Health-related quality of life (HRQoL) was assessed using the Functional Assessment of Cancer Therapy–Prostate (FACT–P) questionnaire. Clinically meaningful change thresholds: ±10 points for FACT-P total score and ±3 points for FACT-P physical wellbeing (PWB) and functional wellbeing (FWB) subscores. Common adverse events (AEs) related to AKT inhibition are summarized descriptively. Results: Of 1012 pts randomized to capi+abi (n=507) or pbo+abi (n=505), 503 in each arm received ≥1 dose; median (range) total treatment duration was 13.6 (0.1–46.6) vs 14.9 (0.1–47.1) months, 47.5% and 53.5% were ongoing capi or pbo. 60.9% and 62.8% in the capi+abi and pbo+abi arm completed the FACT-P. There were no clinically meaningful differences in least-squares mean change from baseline between arms in FACT-P total score (difference 0.4; 95% CI –1.97, 2.78), PWB (–0.4; 95% CI –0.89, 0.14) and FWB (–0.3; 95% CI –1.01, 0.37) subscores. Time to deterioration (TTD) in PWB was faster with capi+abi (HR 1.43 95% CI 1.15, 1.78); TTD in FACT-P total score and FWB showed no difference between arms (HR 1.10 95% CI 0.89, 1.37; HR 1.06 95% CI 0.86, 1.32). Most common AEs in the capi+abi arm occurred early and were manageable (Table). Conclusions: Common capi-associated AEs occur early and are clinically manageable. While pts in the capi+abi arm had more symptomatic AEs (eg diarrhea, rash) consistent with faster decline in self-reported PWB compared with pts in the pbo+abi arm, this did not affect other functional aspects of life (eg work, sleep) and overall HRQoL, allowing for continued treatment with capi+abi. Clinical trial information: NCT04493853 . Diarrhea Rash Hyperglycemia Capi+abi Pbo+abi Capi+abi Pbo+abi Capi+abi Pbo+abi Any grade AE, n (%) 261 (51.9) 40 (8.0) 178 (35.4) 35 (7.0) 191 (38.0) 65 (12.9) Median (IQR) time to onset, days 12 (3–43) 142 (28–339) 13 (11–43) 78 (37–195) 54 (15–114) 114 (71–326) Led to dose reduction, n (%) 22 (4.4) 0 43 (8.5) 2 (0.4) 33 (6.6) 1 (0.2) Led to dose interruption, n (%) 63 (12.5) 1 (0.2) 85 (16.9) 3 (0.6) 55 (10.9) 4 (0.8) Led to dose discontinuation, n (%) 5 (1.0) 0 24 (4.8) 0 5 (1.0) 0 Supportive txt given, n (%) 167 (33.2) 19 (3.8) 146 (29.0) 20 (4.0) 127 (25.2) 23 (4.6) Recovered/recovering, n (%) 238 (47.3) 36 (7.2) 164 (32.6) 28 (5.6) 140 (27.8) 43 (8.5)