Capmatinib in MET exon 14-mutated non-small-cell lung cancer: final results from the open-label, phase 2 GEOMETRY mono-1 trial.

BACKGROUND: Capmatinib has previously shown activity in treatment-naive and previously treated patients with non-small-cell lung cancer (NSCLC) and a MET exon 14-skipping mutation (METex14). Here, we report the final outcomes from the phase 2 GEOMETRY mono-1 study with an aim to provide further evidence for the activity of capmatinib. METHODS: In this non-randomised, multi-cohort, open-label, phase 2 trial conducted in 152 centres and hospitals in 25 countries, with patients treated in 95 centres in 20 countries, eligible patients (aged ≥18 years) with MET-dysregulated, EGFR wild-type, and ALK rearrangement-negative advanced NSCLC (stage IIIB/IV) and an Eastern Cooperative Oncology Group performance status of 0 or 1 were assigned to cohorts (1a, 1b, 2, 3, 4, 5a, 5b, 6 and 7) based on their MET status (METex14 or MET amplification) and previous therapy lines. Patients received capmatinib (400 mg orally twice daily) in 21-day treatment cycles. The primary endpoint was overall response rate by blinded independent central review per Response Evaluation Criteria in Solid Tumours version 1.1 and was performed on the full analysis set (all patients who received at least one dose of capmatinib). Previous reports of this study had published interim or primary data for cohorts 1-7. Here, we report the final clinical outcomes from all METex14 cohorts (4, 5b, 6, and 7) and safety from all study cohorts (1-7). The trial is registered with ClinicalTrials.gov, NCT02414139, and has been completed. FINDINGS: Of 373 treated patients enrolled from June 11, 2015, to March 12, 2020, 160 (97 [61%] female) patients had METex14 NSCLC and were enrolled in four cohorts: 60 treatment-naive (cohorts 5b and 7) and 100 previously treated (cohorts 4 and 6). The overall median study follow-up was 46·4 months (IQR 41·8-65·4) for the treatment-naïve patients and 66·9 months (56·7-73·9) for previously treated patients, respectively. Overall responses were recorded in 41 (68%; 95% CI 55·0-79·7) of 60 treatment-naive patients and 44 (44%; 95% CI 34·1-54·3) of 100 previously treated patients. In all 373 treated patients, the most common treatment-related adverse events were peripheral oedema (n=174; 47%), nausea (n=130; 35%), increased blood creatinine (n=78; 21%), and vomiting (n=74; 20%). Grade 3-4 serious adverse events occurred in 164 (44%) patients, dyspnoea being the most common (18 patients [5%]). Treatment-related deaths occurred in four (1%) patients (one each of cardiac arrest, hepatitis, organising pneumonia, and pneumonitis). No new safety signals were reported. INTERPRETATION: These long-term results support METex14 as a targetable oncogenic driver in NSCLC and add to the evidence supporting capmatinib as a targeted treatment option for treatment-naive and previously treated patients with METex14 NSCLC. FUNDING: Novartis Pharmaceuticals.

Impaired diffusing capacity and COPD incidence in adults with symptoms and normal spirometry.

BACKGROUND: Impaired diffusing capacity of the lung (DLCO) in the absence of post-bronchodilator (BD) airflow obstruction has been proposed as a marker of 'Pre-COPD'. However, the relationship between impaired DLCO and subsequent lung function decline and COPD incidence has not been examined in-depth. METHODS: We conducted an observational study of adults aged between 40 and 70 years who were evaluated at a multi-centre lung function laboratory in Australia between 2014 and 2024. Adults referred with respiratory symptoms or a clinical suspicion of obstructive airways disease with follow-up spirometry obtained ≥ 12 months after the initial assessment were included. The relationship between impaired DLCO and subsequent lung function decline and COPD incidence was assessed among those with normal spirometry at baseline. RESULTS: A total of 266 patients with a mean age of 53.2 (SD 12.8) years were evaluated after a median follow-up of 2.3 [IQR 1.5 to 3.3] years. We found no evidence of an association between impaired DLCO (below the lower limit of normal) and annualised rate of decline in post-BD FEV1 (MD -0.1% predicted per-year, 95%CI -1.3 to 1.2), FVC (-0.4% predicted, 95%CI -1.6 to 0.8) or FEV1/FVC (-0.1% per-year, 95%CI -0.1 to 0.1). The sensitivity of impaired DLCO for COPD incidence was 40%, and specificity 82%. Findings were similar in sub-samples limited to current and former smokers, and when impaired DLCO was defined as < 80% predicted. CONCLUSION: Impaired DLCO was not an effective discriminator of lung function decline or COPD incidence in this real-world cohort.

Customised design of antisense oligonucleotides targeting EGFR driver mutants for personalised treatment of non-small cell lung cancer.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) are currently the standard therapy for patients with non-small cell lung cancer (NSCLC) bearing mutations in epidermal growth factor receptor (EGFR). Unfortunately, drug-acquired resistance is inevitable due to the emergence of new mutations in EGFR. Moreover, the TKI treatment is associated with severe toxicities due to the unspecific inhibition of wild-type (WT) EGFR. Thus, treatment that is customised to an individual's genetic alterations in EGFR may offer greater therapeutic benefits for patients with NSCLC. METHODS: In this study, we demonstrate a new therapeutic strategy utilising customised antisense oligonucleotides (ASOs) to selectively target activating mutations in the EGFR gene in an individualised manner that can overcome drug-resistant mutations. We use extracellular vesicles (EVs) as a vehicle to deliver ASOs to NSCLC cells. FINDINGS: Specifically guided by the mutational profile identified in NSCLC patients, we have successfully developed ASOs that selectively inhibit point mutations in the EGFR gene, including L858R and T790M, while sparing the WT EGFR. Delivery of the EGFR-targeting ASOs by EVs significantly reduced tumour growth in xenograft models of EGFR-L858R/T790M-driven NSCLC. Importantly, we have also shown that EGFR-targeting ASOs exhibit more potent anti-cancer effect than TKIs in NSCLC with EGFR mutations, effectively suppressing a patient-derived TKI-resistant NSCLC tumour. INTERPRETATION: Overall, by harnessing the specificity and efficacy of ASOs, we present an effective and adaptable therapeutic platform for NSCLC treatment. FUNDING: This study was funded by Singapore's Ministry of Health (NMRC/OFIRG/MOH-000643-00, OFIRG21nov-0068, NMRC/OFLCG/002-2018, OFYIRG22jul-0034), National Research Foundation (NRF-NRFI08-2022, NRF-CRP22-2019-0003, NRF-CRP23-2019-0004), A∗STAR, and Ministry of Education.

Key Challenges to Understanding the Burden of Respiratory Syncytial Virus in Older Adults in Southeast Asia, the Middle East, and North Africa: An Expert Perspective.

INTRODUCTION: Respiratory syncytial virus (RSV) is a common, highly contagious pathogen and a leading cause of serious illness among infants and older adults. While existing scientific evidence has predominantly focused on the epidemiology and disease burden of RSV in infants, data in older adults remain limited in some countries, including those in Southeast Asia (SEA) and the Middle East and North Africa (MENA) region. Here, we outline the key challenges for understanding the burden of RSV in older adults in SEA and the MENA region and we propose opportunities for improving understanding and eventually reducing the impact of RSV. MAIN FINDINGS AND CONCLUSIONS: A key challenge identified by the expert group, particularly in older adults, is a lack of awareness (among healthcare professionals, policy makers, and the public) of RSV burden and the associated risks for severe outcomes. This is often confounded by the complexities of underdiagnosis, surveillance limitations, and comorbidities. To address these issues, we suggest medical education initiatives for physicians in SEA and the MENA region to better understand the need to protect older adults from RSV, and encourage more widespread routine testing to better understand the burden of RSV. We also recommend surveillance studies in these regions to provide comprehensive and accurate epidemiological data on RSV in older adults. Finally, in the absence of current surveillance data in these regions, we propose extrapolating existing global data and local pediatric data to inform the likely burden of RSV in older adults. A graphical abstract is available with this article.

Non-small-cell lung cancer.

Non-small-cell lung cancer (NSCLC) is one of the most frequent cancer types and is responsible for the majority of cancer-related deaths worldwide. The management of NSCLC has improved considerably, especially in the past 10 years. The systematic screening of populations at risk with low-dose CT, the implementation of novel surgical and radiotherapeutic techniques and a deeper biological understanding of NSCLC that has led to innovative systemic treatment options have improved the prognosis of patients with NSCLC. In non-metastatic NSCLC, the combination of various perioperative strategies and adjuvant immunotherapy in locally advanced disease seem to enhance cure rates. In metastatic NSCLC, the implementation of novel drugs might prolong disease control together with preserving quality of life. The further development of predictive clinical and genetic markers will be essential for the next steps in individualized treatment concepts.

Smallholder farmers' challenges and opportunities: Implications for agricultural production, environment and food security.

In an era of growing environmental, socioeconomic, and market uncertainties, understanding the adaptive strategies of smallholder farmers is paramount for sustainable agricultural productivity and environmental management efforts. We adopted a mixed-methods approach to investigate the adaptive strategies of smallholders in Northwest Cambodia. Our methodology included downscaled climate projections to project future climate conditions and scenarios, household surveys to collect detailed demographic and socioeconomic data, crop monitoring and record-keeping to gather data on productivity and profitability, and semi-structured interviews to obtain qualitative insights on constraints and adaptation. Our analyses revealed that all smallholders are increasingly vulnerable to climate change which projections reveal will result in more intense and extreme weather events. Specifically, 92% of respondents reported reductions in household income, and 63% indicated the necessity to cut household expenses, which negatively affect agricultural productivity, as evidenced by 33% of respondents reporting declining crop yields and 10% experiencing food shortages. We also uncovered significant differences in farming strategies to mitigate vulnerability among distinct household clusters. Some households prioritise maximising yields through high-expense production strategies, while others focus on optimising inputs to enhance profit-margins, indirectly minimising their environmental impact. These varying strategies have different implications for poverty, food security, and the environment, but were doing very little to mitigate overall vulnerability. To enhance the adaptive capacity of smallholders, policies should target interventions that balance economic growth with environmental sustainability, tailored to the specific needs of different farmer and household types. Promoting the adoption of climate-resilient agricultural practices, investing in water management infrastructure, enhancing access to timely and accurate climate information, and implementing social protection measures are strongly recommended.

Lung cancer screening in never smokers.

PURPOSE OF REVIEW: Low-dose computed tomography (LDCT) lung cancer screening has been established in smokers, but its role in never smokers remains unclear. The differences in lung cancer biology between smokers and nonsmokers highlight the importance of a discriminated approach. This overview focuses on the emerging data and implementation challenges for LDCT screening in nonsmokers. RECENT FINDINGS: The first LDCT screening study in nonsmokers enriched with risk factors demonstrated a lung cancer detection rate double that of the phase 3 trials in smokers. The relative risk of lung cancer detected by LDCT has also been found to be similar amongst female never smokers and male ever smokers in Asia. Majority of lung cancers detected through LDCT screening are stage 0/1, leading to concerns of overdiagnosis. Risk prediction models to enhance individual selection and nodule management could be useful to enhance the utility of LDCT screening in never smokers. SUMMARY: With appropriate risk stratification, LDCT screening in never smokers may attain similar efficacy as compared to smokers. A global effort is needed to generate evidence surrounding optimal screening strategies, as well as health and economic benefits to determine the suitability of widespread implementation.

Five Volts Lithium Batteries with Advanced Carbonate-Based Electrolytes: A Rational Design via a Trio-Functional Addon Materials.

Lithium metal batteries paired with high-voltage LiNi0.5Mn1.5O4 (LNMO) cathodes are a promising energy storage source for achieving enhanced high energy density. Forming durable and robust solid-electrolyte interphase (SEI) and cathode-electrolyte interface (CEI) and the ability to withstand oxidation at high potentials are essential for long-lasting performance. Herein, advanced electrolytes are designed via trio-functional additives to carbonate-based electrolytes for 5 V Li||LNMO and graphite||LNMO cells achieving 88.3% capacity retention after 500 charge-discharge cycles. Theoretical calculations reveal that adding adiponitrile facilitates the presence of more hierarchical DFOB- and PF6 - dual anion structure in the solvation sheath, leading to a faster de-solvation of the Li cation. By combining both fluorine and nitrile additives, an efficient synergistic effect is obtained, generating robust thin inorganic SEI and CEI films, respectively. These films enhance microstructural stability; Li dendrite growth on the Li electrode is being suppressed at the anode side and transition-metals dissolution from the cathode is being mitigated, as evidenced by cryo-transmission electron microscopy and synchrotron studies.

Durability of Response With Selpercatinib in Patients With RET-Activated Thyroid Cancer: Long-Term Safety and Efficacy From LIBRETTO-001.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.LIBRETTO-001 is a registrational phase I/II, single-arm, open-label study of selpercatinib in patients with RET (REarranged during Transfection)-activated cancers (ClinicalTrials.gov identifier: NCT03157128). We present long-term safety and efficacy from LIBRETTO-001 in patients with RET-mutant medullary thyroid cancer (MTC; n = 324) and RET fusion-positive thyroid cancer encompassing different histological subtypes (TC; n = 66). At the data cutoff of January 2023, the objective response rate was 82.5% among patients with cabozantinib/vandetanib-naïve MTC and 95.8% among patients with treatment-naïve TC. At a median follow-up time of 42.4 and 44.0 months in patients with cabozantinib/vandetanib-naïve and pretreated MTC, the median progression-free survival (PFS) was not reached and 41.4 months, respectively. At a median follow-up time of 24.9 and 30.4 months in patients with treatment-naïve and pretreated TC, the median PFS was not reached and 27.4 months, respectively. Three-year PFS rates were 75.2% and 87.3% among patients with cabozantinib/vandetanib-naïve MTC and treatment-naïve TC, respectively. Median PFS was similar to median duration of response for each patient group. The safety profile of selpercatinib was consistent with previous reports. With an additional follow-up of 37 months and 228 more patients from the last disclosure, selpercatinib continued to provide durable and robust responses in treatment-naïve and previously treated patients with RET-mutant MTC and RET fusion-positive TC.

Tepotinib plus osimertinib in patients with EGFR-mutated non-small-cell lung cancer with MET amplification following progression on first-line osimertinib (INSIGHT 2): a multicentre, open-label, phase 2 trial.

BACKGROUND: Patients with EGFR-mutated non-small-cell lung cancer (NSCLC) and MET amplification as a mechanism of resistance to first-line osimertinib have few treatment options. Here, we report the primary analysis of the phase 2 INSIGHT 2 study evaluating tepotinib, a highly selective MET inhibitor, combined with osimertinib in this population. METHODS: This open-label, phase 2 study was conducted at 179 academic centres and community clinics in 17 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1 and advanced or metastatic EGFR-mutated NSCLC of any histology, with MET amplification by tissue biopsy fluorescence in-situ hybridisation (FISH; MET gene copy number of ≥5 or MET-to-CEP7 ratio of ≥2) or liquid biopsy next-generation sequencing (MET plasma gene copy number of ≥2·3), following progression on first-line osimertinib. Patients received oral tepotinib 500 mg plus oral osimertinib 80 mg once daily. The primary endpoint was independently assessed objective response in patients with MET amplification by central FISH treated with tepotinib plus osimertinib with at least 9 months of follow-up. Safety was analysed in patients who received at least one study drug dose. This study is registered with ClinicalTrials.gov, NCT03940703 (enrolment complete). FINDINGS: Between Feb 13, 2020, and Nov 4, 2022, 128 patients (74 [58%] female, 54 [42%] male) were enrolled and initiated tepotinib plus osimertinib. The primary activity analysis population included 98 patients with MET amplification confirmed by central FISH, previous first-line osimertinib and at least 9 months of follow-up (median 12·7 months [IQR 9·9-20·3]). The confirmed objective response rate was 50·0% (95% CI 39·7-60·3; 49 of 98 patients). The most common treatment-related grade 3 or worse adverse events were peripheral oedema (six [5%] of 128 patients), decreased appetite (five [4%]), prolonged electrocardiogram QT interval (five [4%]), and pneumonitis (four [3%]). Serious treatment-related adverse events were reported in 16 (13%) patients. Deaths of four (3%) patients were assessed as potentially related to either trial drug by the investigator due to pneumonitis (two [2%] patients), decreased platelet count (one [1%]), respiratory failure (one [1%]), and dyspnoea (one [1%]); one death was attributed to both pneumonitis and dyspnoea. INTERPRETATION: Tepotinib plus osimertinib showed promising activity and acceptable safety in patients with EGFR-mutated NSCLC and MET amplification as a mechanism of resistance to first-line osimertinib, suggesting a potential chemotherapy-sparing oral targeted therapy option that should be further investigated. FUNDING: Merck (CrossRef Funder ID: 10.13039/100009945).

Therapeutic application of extracellular vesicular EGFR isoform D as a co-drug to target squamous cell cancers with tyrosine kinase inhibitors.

Targeting wild-type epidermal growth factor receptor (EGFR) using tyrosine kinase inhibitors (TKIs) never achieved its purported success in cancers such as head and neck squamous cell carcinoma, which are largely EGFR-dependent. We had previously shown that exceptional responders to TKIs have a genetic aberration that results in overexpression of an EGFR splice variant, isoform D (IsoD). IsoD lacks an integral transmembrane and kinase domain and is secreted in extracellular vesicles (EVs) in TKI-sensitive patient-derived cultures. Remarkably, the exquisite sensitivity to TKIs could be transferred to TKI-resistant tumor cells, and IsoD protein in the EV is necessary and sufficient to transfer the phenotype in vitro and in vivo across multiple models and drugs. This drug response requires an intact endocytic mechanism, binding to full-length EGFR, and signaling through Src-phosphorylation within the endosomal compartment. We propose a therapeutic strategy using EVs containing EGFR IsoD as a co-drug to expand the use of TKI therapy to EGFR-driven cancers.

Identifying the physiological traits associated with DNA marker using genome wide association in wheat under heat stress.

Heat stress poses a significant environmental challenge that profoundly impacts wheat productivity. It disrupts vital physiological processes such as photosynthesis, by impeding the functionality of the photosynthetic apparatus and compromising plasma membrane stability, thereby detrimentally affecting grain development in wheat. The scarcity of identified marker trait associations pertinent to thermotolerance presents a formidable obstacle in the development of marker-assisted selection strategies against heat stress. To address this, wheat accessions were systematically exposed to both normal and heat stress conditions and phenotypic data were collected on physiological traits including proline content, canopy temperature depression, cell membrane injury, photosynthetic rate, transpiration rate (at vegetative and reproductive stage and 'stay-green'. Principal component analysis elucidated the most significant contributors being proline content, transpiration rate, and canopy temperature depression, which exhibited a synergistic relationship with grain yield. Remarkably, cluster analysis delineated the wheat accessions into four discrete groups based on physiological attributes. Moreover, to explore the relationship between physiological traits and DNA markers, 158 wheat accessions were genotyped with 186 SSRs. Allelic frequency and polymorphic information content value were found to be highest on genome A (4.94 and 0.688), chromosome 1A (5.00 and 0.712), and marker Xgwm44 (13.0 and 0.916). Population structure, principal coordinate analysis and cluster analysis also partitioned the wheat accessions into four subpopulations based on genotypic data, highlighting their genetic homogeneity. Population diversity and presence of linkage disequilibrium established the suitability of population for association mapping. Additionally, linkage disequilibrium decay was most pronounced within a 15-20 cM region on chromosome 1A. Association mapping revealed highly significant marker trait associations at Bonferroni correction P < 0.00027. Markers Xwmc418 (located on chromosome 3D) and Xgwm233 (chromosome 7A) demonstrated associations with transpiration rate, while marker Xgwm494 (chromosome 3A) exhibited an association with photosynthetic rates at both vegetative and reproductive stages under heat stress conditions. Additionally, markers Xwmc201 (chromosome 6A) and Xcfa2129 (chromosome 1A) displayed robust associations with canopy temperature depression, while markers Xbarc163 (chromosome 4B) and Xbarc49 (chromosome 5A) were strongly associated with cell membrane injury at both stages. Notably, marker Xbarc49 (chromosome 5A) exhibited a significant association with the 'stay-green' trait under heat stress conditions. These results offers the potential utility in marker-assisted selection, gene pyramiding and genomic selection models to predict performance of wheat accession under heat stress conditions.

Training immunophenotyping deep learning models with the same-section ground truth cell label derivation method improves virtual staining accuracy.

Introduction: Deep learning (DL) models predicting biomarker expression in images of hematoxylin and eosin (H&E)-stained tissues can improve access to multi-marker immunophenotyping, crucial for therapeutic monitoring, biomarker discovery, and personalized treatment development. Conventionally, these models are trained on ground truth cell labels derived from IHC-stained tissue sections adjacent to H&E-stained ones, which might be less accurate than labels from the same section. Although many such DL models have been developed, the impact of ground truth cell label derivation methods on their performance has not been studied. Methodology: In this study, we assess the impact of cell label derivation on H&E model performance, with CD3+ T-cells in lung cancer tissues as a proof-of-concept. We compare two Pix2Pix generative adversarial network (P2P-GAN)-based virtual staining models: one trained with cell labels obtained from the same tissue section as the H&E-stained section (the 'same-section' model) and one trained on cell labels from an adjacent tissue section (the 'serial-section' model). Results: We show that the same-section model exhibited significantly improved prediction performance compared to the 'serial-section' model. Furthermore, the same-section model outperformed the serial-section model in stratifying lung cancer patients within a public lung cancer cohort based on survival outcomes, demonstrating its potential clinical utility. Discussion: Collectively, our findings suggest that employing ground truth cell labels obtained through the same-section approach boosts immunophenotyping DL solutions.

Integrated care for children and young people with special health and care needs: a systematic review.

CONTEXT: There is a dearth of high-quality evidence on integrated, coordinated and cost-effective care for children with special health and care needs (CSHCN). OBJECTIVE: To assess the effectiveness of integrated/coordinated care models for CSHCN. DATA SOURCES: Embase, Ovid Medline(R), HMIC Health Management Information Consortium, Maternity & Infant Care Database (MIDIRS), PsycARTICLES, PsycINFO, Social Policy and Practice, Cochrane Central Register of Controlled Trials (CENTRAL), Global Health and PubMed. STUDY SELECTION: Inclusion criteria comprised (1) randomised trials, including cluster randomised trials; (2) an integrated/coordinated care intervention; (3) for children and young people under 25 with special healthcare needs including medical complexity; (4) assessing child-centred outcomes, health-related quality of life among parents and carers, and health or social care use, processes of care and satisfaction with care. DATA EXTRACTION: Data were extracted and assessed by two researchers, and descriptive data were synthesised according to outcome and intervention. RESULTS: 14 randomised controlled studies were included. Seven out of the 14 studies had a dedicated key worker/care coordinator as a vital part of the integrated/coordinated care intervention; however, the certainty of evidence for all outcomes was either 'low' or 'very low'. LIMITATIONS: Included studies were mostly from high-income countries. Variable study outcomes and quality of evidence precluded meta-analysis. CONCLUSIONS: Limited evidence favours integrated care for CSHCN using a dedicated key worker/care coordinator; however, heterogeneity in study outcomes and definitions of CSHCN limit the strength and utility of evidence obtained. Recommendations are made for improving integrated care practice, research and evaluation which are important for evidence-based health services for CSHCN. PROSPERO REGISTRATION NUMBER: CRD42020209320.

Synergy of Oxygen Octahedra Distortion and Polar Nanodomains Induced Emergent Electrocaloric Effect in NaNbO3-Based Ceramics.

High-performance electrocaloric materials are essential for the development of solid-state cooling technologies; however, the contradiction of the electrocaloric effect (ECE) and temperature span in ferroelectrics frustrates practical applications. In this work, through modulating oxygen octahedra distortion and short-range polar nanodomains with moderate coupling strength, an EC value of ΔT ∼ 0.30 K with an ultrawide temperature span of 85 K is obtained in the x = 0.04 composition [(0.88 - x)NaNbO3-0.12BaTiO3-xLiSbO3 (x = 0-0.06)]. The LiSbO3 dopant induces a P4bm-to-R3cH phase transition and intensifies the oxygen octahedra distortion degree, accompanied by the ferroelectric domain smashing into polar nanodomains. Also, LiSbO3 addition enhances the relaxation degree with a downshift of Tfd (ferroelectric-to-diffuse phase transition temperature) and TJ (temperature of the maximal current density value), and Tfd is shifted to near room temperature with an absence of TJ in x = 0.04. Local energy barriers induced by oxygen octahedra distortion inhibit the phase transition in conjunction with activation of short-range polar order switching under thermal stimuli, which is the underlying mechanism for an excellent EC performance for x = 0.04. This work not only clarifies that ferroelectrics with oxygen octahedra distortion and short-range polar order are expected to achieve remarkable EC performances but also provides a design strategy to seek emergent EC behaviors in complex oxygen-octahedra-distortion materials.

Capmatinib plus nazartinib in patients with EGFR-mutated non-small cell lung cancer.

PURPOSE: This phase 1b/2 trial evaluated the efficacy and safety of capmatinib plus nazartinib in patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC). METHODS: In phase 1b, patients with progression on first-/second-generation EGFR-TKIs received escalating doses of capmatinib 200-400 mg bid plus nazartinib 50-150 mg qd. Once the MTD/RP2D was declared, phase 2 commenced with patient enrollment into groups according to mutation status and prior lines of treatment: group 1 (fasted; EGFR-TKI resistant; 1-3 prior lines; EGFRL858R/ex19del; any T790M/MET); group 2 (fasted; EGFR-TKI naïve; 0-2 prior lines; de novo T790M+; any MET); group 3 (fasted; treatment-naïve; EGFRL858R/ex19del; T790M-; any MET); group 4 (with food; 0-2 prior lines; EGFRL858R/ex19del; any T790M/MET). Primary endpoints in phase 2 were investigator-assessed overall response rate (ORR) per RECIST v1.1 (groups 1-3), safety, and tolerability of the combination with food (group 4). Efficacy was assessed by T790M and MET status for a subgroup of patients. RESULTS: The RP2D was capmatinib 400 mg bid plus nazartinib 100 mg qd. In phase 2 (n = 144), the ORR was 28.8 %, 33.3 %, 61.7 %, and 42.9 % in groups 1 (n = 52), 2 (n = 3), 3 (n = 47), and 4 (n = 42), respectively. In group 1 +phase 1b RP2D, the ORR was 45.8 %, 26.2 %, 37.9 %, and 32.4 % in MET+ (n = 24), MET- (n = 42), T790M+ (n = 29), and T790M- (n = 34) patients. Most common any-grade treatment-related adverse events (≥25 %; n = 144) were peripheral edema (54.9 %), nausea (41.7 %), diarrhea (34.0 %), and maculopapular rash (25.0 %). CONCLUSION: Capmatinib plus nazartinib showed antitumor activity in patients with EGFR-TKI-resistant, EGFR-mutated NSCLC. The overall safety profile was acceptable. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02335944.

PARP4 interacts with hnRNPM to regulate splicing during lung cancer progression.

BACKGROUND: The identification of cancer driver genes from sequencing data has been crucial in deepening our understanding of tumor biology and expanding targeted therapy options. However, apart from the most commonly altered genes, the mechanisms underlying the contribution of other mutations to cancer acquisition remain understudied. Leveraging on our whole-exome sequencing of the largest Asian lung adenocarcinoma (LUAD) cohort (n = 302), we now functionally assess the mechanistic role of a novel driver, PARP4. METHODS: In vitro and in vivo tumorigenicity assays were used to study the functional effects of PARP4 loss and mutation in multiple lung cancer cell lines. Interactomics analysis by quantitative mass spectrometry was conducted to identify PARP4's interaction partners. Transcriptomic data from cell lines and patient tumors were used to investigate splicing alterations. RESULTS: PARP4 depletion or mutation (I1039T) promotes the tumorigenicity of KRAS- or EGFR-driven lung cancer cells. Disruption of the vault complex, with which PARP4 is commonly associated, did not alter tumorigenicity, indicating that PARP4's tumor suppressive activity is mediated independently. The splicing regulator hnRNPM is a potentially novel PARP4 interaction partner, the loss of which likewise promotes tumor formation. hnRNPM loss results in splicing perturbations, with a propensity for dysregulated intronic splicing that was similarly observed in PARP4 knockdown cells and in LUAD cohort patients with PARP4 copy number loss. CONCLUSIONS: PARP4 is a novel modulator of lung adenocarcinoma, where its tumor suppressive activity is mediated not through the vault complex-unlike conventionally thought, but in association with its novel interaction partner hnRNPM, thus suggesting a role for splicing dysregulation in LUAD tumorigenesis.

In-Plane Mesoporous 3D Flower-Like Mo2Ti2C3Clx MXene Anodes for Li-Ion Batteries: From Structure to Performance.

MXenes are known for their exceptional electrical conductivity and surface functionality, gaining interest as promising anode materials for Li-ion batteries. However, conventional 2D multilayered MXenes often exhibit limited electrochemical applicability due to slow ion transport kinetics and low structural stability. Addressing these challenges, this study develops a 3D flower-type double transition metal MXene, Mo2Ti2C3Clx, with precisely engineered in-plane mesoporosity using HF-free Lewis acid-assisted molten salt method, coupled with intercalation and freeze-drying. The molar ratio of Lewis acid to eutectic salts is meticulously controlled to create the mesoporosity, which is preserved through freeze-drying. Molecular dynamics (MD) simulations assess the impact of in-plane pore size on the structure and transport dynamics of electrolyte components. Density functional theory (DFT) shows that chlorine surface functional groups significantly reduce Li-ion diffusion barriers, thereby enhancing ion transport and battery performance. Electrochemical evaluations reveal that small-sized (2-5 nm) mesoporous Mo2Ti2C3Clx achieves a specific capacity of 324 mAh g-1 at 0.2 A g-1 and maintains 97% capacity after 500 cycles at 0.5 A g-1, outperforming larger-pored (10 nm) and non-porous variants. This research highlights a scalable strategy for designing mesoporous materials that optimize ion transport and structural stability, essential for advancing next-generation high-performance energy storage solutions.