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Mitochondrially Transcribed DsRNA Mediates Manganese-Induced Neuroinflammation

Manganese is an essential trace element required for various biological functions but in excess is neurotoxic and leads to significant health concerns. The mechanisms underlying manganese neurotoxicity remain poorly understood. Neuropathological studies of affected brain regions reveal astrogliosis, neuronal loss, and neuroinflammation. Here, we present a novel manganese-dependent mechanism linking mitochondrial dysfunction to neuroinflammation. We found that manganese disruption of the mitochondrial transcriptome processing results in the accumulation of double-stranded RNA (dsRNA). This dsRNA is released into the cytoplasm, where it activates the cytosolic sensor MDA5, triggering type I interferon responses and inflammatory cytokine production. This mechanism is evident in 100 d human cerebral organoids, where manganese increased mitochondrial dsRNA and induced inflammatory responses in mature astrocytes. Similarly, we observed an increase in mitochondrial dsRNA content, the activation of an inflammatory transcriptome and the production of cytokines in female and male mouse brains carrying mutations in the Slc30a10 gene, a model for human hypermanganesemia with dystonia 1 disorder. These findings highlight the previously unrecognized role of mitochondrial dsRNA in manganese-induced neuroinflammation and provide insights into the molecular pathogenesis of manganism. We propose that this mitochondrial dsRNA-induced inflammatory pathway could be active in other neurological diseases caused by environmental or genetic factors.

Synthesis, biological evaluation and detailed computational studies of N-sulfonyl indole-based dihydrothiazoles against colorectal carcinoma

SUPPORT+ digital self-management and clinical support for advanced cancer: A randomized controlled trial.

LBA12008 Background: Patients with advanced cancer often experience distressing symptoms that impair HRQoL and lead to emergency department (ED) visits and hospitalizations. Digital symptom-monitoring tools enable earlier detection of symptoms, yet evidence in palliative care remains limited. This study evaluated whether SUPPORT+, a mobile app incorporating weekly symptom reporting using the Integrated Palliative Care Outcome Scale (IPOS), automated self-management guidance, and nurse follow-up for severe symptoms, improves outcomes when added to usual care for community-dwelling patients with advanced cancer. Methods: A multi-centre RCT was conducted across 6 palliative care clinics in Hong Kong (Jan 2023–Feb 2025). Patients with advanced cancers no longer receiving systemic treatment were randomized 1:1 to SUPPORT+ or usual care for 18 weeks. The primary outcome was change in HRQoL (EQ-5D-5L). Secondary outcomes included ECOG PS, ED visits, and hospitalizations. Results: A total of 633 patients were enrolled (315 intervention; 318 control), median age 79 (range 31–103), with 47.4% male. HRQoL was better maintained in SUPPORT+: EQ-5D-5L index declined from 0.59 at baseline to 0.52 at week 18 vs. 0.62 to 0.37 in usual care (mean difference −0.18; p<0.001). EQ-VAS remained more stable (68.7 to 65.8 vs. 68.9 to 59.5; mean difference −6.54, p<0.001). ECOG PS deterioration was less common (12.4% vs. 18.9%; p=0.016). ED visits were similar. Hospitalization outcomes favoured SUPPORT+, with more reductions in admissions and shorter lengths of stay (both p≤0.001). Conclusions: SUPPORT+ maintained HRQoL, preserved PS, and reduced hospitalizations in advanced cancer. Digital symptom monitoring with automated self-management and timely healthcare support is a promising strategy to strengthen community-based supportive care. Clinical trial information: HKUCTR-3116. Proportion of patients in the SUPPORT+ arm and control (usual care) arm with changes in HRQoL, self-efficacy, emergency department visit, hospitalization episodes and duration. Intervention Group N=315 Control Group N=318 P-value no. % no. % Primary Endpoint: EQ-5D-5L index (change ≥0.11) Improved 59 18.73% 14 4.4% <0.001 No change 137 43.49% 129 40.57% Worsen 119 37.78% 175 55.03% EQ-5D-5L VAS (change ≥6) Improved 80 25.40% 48 15.09% 0.002 No change 114 36.19% 112 35.22% Worsen 121 38.41% 158 49.69% Secondary Endpoints: Self-efficacy Improved 121 38.41% 65 20.44% <0.001 No change 18 5.71% 26 8.18% Worsen 176 55.87% 227 71.38% Emergency Department Visits Reduced 85 26.98% 76 23.90% 0.167 No change 171 54.29% 163 51.26% Increased 59 18.73% 79 24.84% Hospitalization Episodes Reduced 89 28.25% 70 22.01% 0.001 No change 174 55.24% 157 49.37% Increased 52 16.51% 91 28.62% Hospitalization Days Reduced 98 31.11% 70 22.01% <0.001 No change 162 51.43% 136 42.77% Increased 55 17.46% 112 35.22% ECOG Improved 6 1.90% 13 4.09% 0.016 No change 270 85.71% 245 77.04% Worsen 39 12.38% 60 18.87%

Imaging of a van der Waals spin-orbit torque system using spin ensembles in hBN

Abstract Recently, optically active spin defects embedded in two-dimensional (2D) van der Waals (vdW) crystals have emerged as a transformative quantum sensing platform to explore cutting-edge materials science. Taking advantage of excellent solid-state integrability, this new class of spin defects can be readily arranged in nanoscale proximity to target materials, showing great promise for realizing in-situ quantum sensing of microscopic spin and charge behaviors in vdW heterostructures. Here we report hexagonal boron nitride-based quantum imaging of field-free deterministic magnetic switching and electric current distributions in an all-vdW spin-orbit torque (SOT) system. By visualizing variations of nanoscale magnetic stray field profile of room-temperature 2D magnet Fe 3 GaTe 2 under different SOT conditions, we show how the magnetic switching evolves from deterministic to stochastic behavior due to the interplay between spin orientations, anisotropy and Joule heating. Micromagnetic simulations rationalize our results well, revealing the role of field-like SOT in inhibiting thermal fluctuation driven stochastic switching and chaotic multi-domain competition. This understanding, which is otherwise difficult to access by conventional transport measurements, offers valuable insights into material design, testing, and performance evaluation of next-generation vdW spintronic devices.

Ladderanes: Stepping Up as Nonclassical <i>ortho</i> -Substituted Benzene Bioisosteres

Conservative Oxygen for Unresponsive Patients after Cardiac Arrest

Human macrophage adhesion is significantly higher on SIBS based glaucoma microshunts than on common intraocular lens materials in vitro

Daraxonrasib, a RAS(ON) multi-selective inhibitor vs chemotherapy in previously treated metastatic pancreatic adenocarcinoma (mPDAC): Primary and final analysis from the phase 3 RASolute 302 study.

LBA5 Background: Available 2L therapies offer limited clinical benefit in mPDAC with reported mPFS of 3–4 mo and mOS of 6–7 mo. Aberrant RAS pathway activation is the key driver of PDAC, with oncogenic RAS mutations (mut) identified in &gt;90% of cases, most commonly at codon G12. Daraxonrasib is an oral, RAS(ON) multi-selective, tri-complex inhibitor of the active, GTP-bound state of mutant and wild type RAS. Methods: RASolute 302 (NCT06625320) is a global, randomized, open-label, Ph 3 study in pts with 2L mPDAC and ECOG PS 0-1. Pts were randomized 1:1 to receive daraxonrasib 300 mg PO QD or investigator’s choice of SOC cytotoxic chemo. Dual primary endpoints were OS and PFS by BICR in the RAS G12 mutant (RAS G12) population. Key secondary endpoints included OS and PFS by BICR in the overall population, ORR by BICR in RAS G12 and overall populations. Results: 248 pts were randomized to daraxonrasib and 252 to chemo. Baseline characteristics were balanced between arms. At data cutoff (Feb 10, 2026; mFU: 8.5 mo), all primary and key secondary endpoints were met. Statistically significant, clinically meaningful improvements in OS and PFS were observed with daraxonrasib vs chemo in the RAS G12 and overall populations (Table). Gr ≥3 TRAEs occurred in 43.6% of pts receiving daraxonrasib vs 57.5% receiving chemo. The most common (≥10%) Gr ≥3 TRAEs were rash (13.7%) and stomatitis (12.0%) for daraxonrasib; neutrophil decrease (18.2%) and anemia (16.4%) for chemo. TRSAEs occurred in 10.8% of pts receiving daraxonrasib vs 18.7% receiving chemo. Discontinuation due to TRAEs occurred in 1.2% of pts for daraxonrasib vs 11.2% for chemo. Median/mean daraxonrasib dose intensity was 93.1%/84.7%. Conclusions: Daraxonrasib demonstrated unprecedented improvements in OS and PFS vs chemo in pts with 2L mPDAC with or without an identified tumor RAS mut. Daraxonrasib was generally well tolerated, with a manageable safety profile and with no new safety signals. Results support daraxonrasib as the new SOC for 2L mPDAC. Clinical trial information: NCT06625320 . RAS G12 Overall b Daraxonrasibn=228 Chemo n=231 Daraxonrasib n=248 Chemo n=252 OS Median; mos(95% CI) 13.2(10.0–NE) 6.6(5.4–8.2) 13.2(10.0–NE) 6.7(5.8–8.0) HR(95% CI)P-value 0.40(0.30-0.54)&lt;0.0001 0.40(0.30-0.53)&lt;0.0001 PFS a Median; mos(95% CI) 7.3(6.3–8.1) 3.5(2.9–3.8) 7.2(5.7–7.5) 3.6(2.9–4.2) HR(95% CI)P-value 0.45(0.34-0.59)&lt;0.0001 0.49(0.38-0.64)&lt;0.0001 ORR a %(95% CI) 33.2(27.0–39.9) 11.8(7.8–16.8) 31.6(25.8–38.0) 11.2(7.5–15.9) a By BICR. b RAS G12, G13 or Q61 mut or no RAS mut identified.

Synthesis of bundle copolymers as an emergent class of copolymer architecture

Biomimetic Synthesis of Seven Halenaquinone Meroterpenoids

Exa-cel in Children with Transfusion-Dependent β-Thalassemia or Sickle Cell Disease

Development of chemically modified clinoptilolite granules for enhanced ammonia removal

BREAKWATER: Progression-free and overall survival analyses of first-line (1L) encorafenib + cetuximab (EC) + FOLFIRI in BRAF V600E-mutant metastatic colorectal cancer (mCRC).

LBA3503 Background: Leucovorin/5-FU in combination with oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) are common chemotherapies (chemo) used in 1L treatment (tx) of mCRC. In patients (pts) with BRAF V600E-mutant mCRC, BREAKWATER Phase 3 demonstrated clinically meaningful and statistically significantly improved ORR by blinded independent central review (BICR), PFS by BICR, and OS with 1L EC+mFOLFOX6 vs chemo ± bevacizumab (bev) (Kopetz Nat Med 2025; Elez N Engl J Med 2025). The BREAKWATER safety lead-in previously showed that EC+FOLFIRI was tolerable with promising antitumor activity. BREAKWATER Cohort 3 was therefore conducted to study EC+FOLFIRI. The primary endpoint (EP) of BREAKWATER Cohort 3 was met, demonstrating clinically meaningful and statistically significant improvement in confirmed ORR by BICR with EC+FOLFIRI (64.4%) vs FOLFIRI±bev (39.2%; control) (odds ratio 2.76 [95% CI 1.42, 5.35; one-sided P =0.001]) (Kopetz ASCO GI 2026). Reported here are PFS by BICR (key secondary EP), and updated OS and safety data from BREAKWATER Cohort 3. Methods: Eligible pts in Cohort 3 had untreated BRAF V600E-mutant mCRC, measurable disease (RECIST 1.1), and ECOG PS 0-1. Pts were randomized 1:1 to receive EC+FOLFIRI or control. The primary EP was ORR by BICR. The key secondary EP was PFS by BICR; other secondary EPs included OS and safety. Results: 147 pts were randomized to EC+FOLFIRI or control; the median follow-up for PFS was 18.0 and 14.4 mo, respectively, for OS it was 20.6 and 20.7 mo, respectively (data cutoff: Jan 6, 2026). Baseline demographics and disease characteristics were generally balanced between arms. EC+FOLFIRI demonstrated a clinically meaningful and statistically significant PFS improvement vs control, meeting the key secondary EP (Table). Prolonged OS was observed (Table). The median duration of study tx was 67.9 wk for EC+FOLFIRI and 32.1 wk for control. Discontinuation of chemo (± bev as appropriate for the respective tx arms) due to AEs was similar between arms (14% [EC+FOLFIRI] vs 10% [control]). Conclusions: BREAKWATER Cohort 3 demonstrated clinically meaningful and statistically significant ORR and PFS improvements and prolonged OS with EC+FOLFIRI vs control. The safety profile was consistent with that known for each agent with no new safety signals. EC+FOLFIRI expands practice-changing standard-of-care options to deliver pt-centered care for pts with BRAF V600E-mutant mCRC. Clinical trial information: NCT04607421 . EC+FOLFIRI (n=73) Control (n=74) mPFS (95% CI), mo 15.2 (13.6, NE) 8.3 (6.9, 9.8) PFS HR a (95% CI) 0.44 (0.27, 0.70)One-sided P =0.0002 mOS (95% CI), mo NE (21.0, NE) 20.3 (13.2, NE) OS HR a (95% CI) 0.56 (0.34, 0.94) 18-mo OS rate (95% CI), % 72.0 (60.0, 80.9) 54.5 (42.0, 65.4) n=71 n=68 Serious TEAEs, % 49 44 Maximum Grade 3/4 TEAEs, % 70 81 NE, not estimable; TEAE, tx-emergent adverse event. a Stratified by ECOG PS (0 vs 1) at randomization.

Flexural phonon instability defines intrinsic van der Waals elastic limits in the interlayer direction

Ring-Opening Metathesis Polymerization of Caged FLP Monomers and Uncaged Alkene Macromonomers

Carbocisteine or Hypertonic Saline for Acute Respiratory Failure

Knowledge, attitudes, and practices of anesthesiology healthcare professionals regarding crisis resource management in Shanghai, China: a cross-sectional study

A randomized, open-label, parallel-controlled phase 3 trial of benmelstobart plus chemotherapy and anlotinib for first-line treatment of advanced non-squamous non–small cell lung cancer.

LBA8507 Background: PD-1/PD-L1 inhibitors plus chemotherapy remain standard first-line therapy for EGFR/ALK/ROS1-wild type advanced non-squamous non-small cell lung cancer (nsq-NSCLC). Pre-clinical data suggest angiogenesis inhibitors may potentiate immune checkpoint inhibitors (ICIs). This phase 3 trial evaluated sequential benmelstobart (anti-PD-L1 mAb) plus chemo followed by benmelstobart plus anlotinib versus standard therapy for PFS improvement in this patient population. Methods: TQB2450-III-11 (NCT05346952) is a randomized, open-label, parallel-controlled phase 3 trial. Eligible patients were diagnosed with locally advanced (stage IIIB/C, unfit for surgery or curative-intent chemoradiotherapy) or metastatic nsq-NSCLC. Previous systemic treatment for advanced disease was not allowed. Other key inclusion criteria included ECOG PS of 0-1, aged 18-75 and no EGFR mutations, no ALK or ROS1 rearrangements. Patients were stratified by PD-L1 TPS level (＜1%/1-49%/≥50%) and randomized 1:1 to receive benmelstobart or tislelizumab plus platinum and pemetrexed for 4 cycles, then followed by maintenance with benmelstobart plus anlotinib and pemetrexed or tislelizumab plus pemetrexed until disease progression or unacceptable toxicities. Anlotinib dosing was 10 mg, while benmelstobart or tislelizumab was given at a dose of 1200 mg or 200 mg Q3W. The primary endpoint was PFS by independent review committee according to the RECIST version 1.1. Results: From January 24, 2022 to May 8, 2023, 596 eligible patients were randomized 1:1 to benmelstobart group and tislelizumab group. Baseline characteristics were well balanced between two groups. Median PFS was significantly improved in benmelstobart group (14.42 months, 95% CI, 12.35–NE) versus tislelizumab group (8.34 months, 95% CI, 6.97–12.39), HR 0.67 (95% CI, 0.52–0.86; P = 0.0017). The subgroup analysis showed that PFS benefit favored benmelstobart group in almost all subgroups, particularly in patients with ECOG PS 0 (HR 0.36, 0.20-0.65) and PD-L1 TPS ＜1% (HR 0.61, 0.43-0.86). OS was immature. Safety profiles were similar in two groups. Treatment-emergent adverse events of any grade was 92.28% (benmelstobart group) and 90.94% (tislelizumab group) respectively. ≥Grade 3 treatment-related adverse events was 56.38% (benmelstobart group) and 48.66% (tislelizumab group). Immune-related adverse events was 19.13% (benmelstobart group) and 18.46% (tislelizumab group). Conclusions: Benmelstobart in combination with chemotherapy followed by sequential combination with anlotinib significantly improved PFS compared to tislelizumab in combination with chemotherapy followed by sequential tislelizumab, with a manageable safety profile. It might be a new first-line treatment for nsq-NSCLC. Clinical trial information: NCT05346952 .

Natural language processing models for patient-centered summaries of prostatectomy pathology reports

Ramelteon for prevention of postoperative delirium in elderly cancer patients: A randomized, double-blind, placebo-controlled multicenter trial, JORTC-PON02/J-SUPPORT2103/NCCH2103.

LBA12002 Background: Delirium is a common and serious complication after major cancer surgery in older adults. Current guidelines, including the American Psychiatric Association guideline, do not recommend routine pharmacological prevention because of insufficient high-quality evidence. Ramelteon, a melatonin receptor agonist with a favorable safety profile, has suggested potential benefit in critically ill populations but has shown inconsistent results for prevention of postoperative delirium. Methods: This randomized, double-blind, placebo-controlled multicenter phase III trial enrolled cancer patients aged ≥65 years undergoing surgery under general anesthesia. Patients received ramelteon 8 mg or placebo nightly from 4–8 days before surgery through postoperative day 4. Randomization used minimization with prespecified stratification factors (age ≥75 years, surgical duration ≥6 h, benzodiazepine use, and study site). Guideline-based multicomponent delirium prevention care was implemented in all patients. The planned sample size was 678 patients aged ≥75 years (primary analysis set) plus 88 aged 65–74 years. The primary endpoint was DSM-5–defined delirium within 5 days after surgery. Between-group differences were analyzed using a Cochran–Mantel–Haenszel test adjusted for stratification factors. Results: Among patients aged ≥75 years, postoperative delirium occurred in 22.47% (71/316) of patients receiving ramelteon and 22.76% (71/312) receiving placebo, with no significant difference between groups (adjusted risk difference, ramelteon minus placebo, 0.05%; 95% CI, -6.50% to 6.59%; P = 0.9881). Among patients aged ≥65 years, delirium occurred in 22.54% (80/355) in the ramelteon group and 21.19% (75/354) in the placebo group (adjusted risk difference, ramelteon minus placebo, 1.57%; 95% CI, -4.52% to 7.65%; P = 0.6098). Conclusion: In this phase III randomized controlled trial, ramelteon did not reduce the incidence of postoperative delirium in older adults undergoing major cancer surgery, and these findings do not support routine pharmacological prevention with ramelteon in this setting. Clinical trial information: jRCTs031210673. Clinical trial information: jRCTs031210673 . Delirium within 5 days after surgery. Item Description Primary endpoint result (≥75 y) 22.47% (71/316) with ramelteon vs 22.76% (71/312) with placebo Secondary endpoint result (≥65 y) 22.54% (80/355) with ramelteon vs 21.19% (75/354) with placebo