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Repairing bone defects is a complex cascade reaction process, as immune system regulation, vascular growth, and osteogenic differentiation are essential. Thus, developing a tissue-engineered biomaterial that caters to the complex healing process of bone regeneration remains a major clinical challenge. In the study, Ca 2+ -TA-rGO (CTAG)/GelMA hydrogels were synthesized by binding Ca 2+ using metal chelation to graphene oxide (GO) nanosheets reduced by tannic acid (TA-rGO) and doping them into gelatin methacrylate (GelMA) hydrogels. TA and rGO exhibited biocompatibility and immunomodulatory properties in this composite, while Ca 2+ promoted bone formation and angiogenesis. This novel nanocomposite hydrogel demonstrated good mechanical properties, degradability, and conductivity, and it could achieve slow Ca 2+ release during bone regeneration. Both in vitro and in vivo experiments revealed that CTAG/GelMA hydrogel modulated macrophage reprogramming and induced a shift from macrophages to healing-promoting M2 macrophages during the inflammatory phase, promoted vascular neovascularization, and facilitated osteoblast differentiation during bone formation. Moreover, CTAG/GelMA hydrogel could downregulate the NF-κB signaling pathway, offering new insights into regulating macrophage reprogramming-osteogenic crosstalk. Conclusively, this novel multifunctional nanocomposite hydrogel provides a multistage treatment for bone and orchestrates macrophage reprogramming-osteogenic crosstalk to boost bone repair. Graphical Abstract

The ADJUVANT study reported the comparative superiority of adjuvant gefitinib over chemotherapy in disease-free survival of resected EGFR -mutant stage II–IIIA non-small cell lung cancer (NSCLC). However, not all patients experienced favorable clinical outcomes with tyrosine kinase inhibitors (TKI), raising the necessity for further biomarker assessment. In this work, by comprehensive genomic profiling of 171 tumor tissues from the ADJUVANT trial, five predictive biomarkers are identified ( TP53 exon4/5 mutations, RB1 alterations, and copy number gains of NKX2-1 , CDK4 , and MYC ). Then we integrate them into the Multiple-gene INdex to Evaluate the Relative benefit of Various Adjuvant therapies (MINERVA) score, which categorizes patients into three subgroups with relative disease-free survival and overall survival benefits from either adjuvant gefitinib or chemotherapy (Highly TKI-Preferable, TKI-Preferable, and Chemotherapy-Preferable groups). This study demonstrates that predictive genomic signatures could potentially stratify resected EGFR -mutant NSCLC patients and provide precise guidance towards future personalized adjuvant therapy. Adjuvant gefitinib improves outcomes in non-small cell lung cancer (NSCLC) patients compared to chemotherapy, but not in all cases. Here, the authors find genomic biomarkers of response to gefitinib in NSCLC patients from the ADJUVANT trial, and propose a score to stratify them by potential benefit from the treatment.

Modulating a favorable inflammatory microenvironment that facilitates the recovery of degenerated discs is a key strategy in the treatment of intervertebral disc (IVD) degeneration (IDD). More interestingly, well-mechanized tissue-engineered scaffolds have been proven in recent years to be capable of sensing mechanical transduction to enhance the proliferation and activation of nucleus pulposus cells (NPC) and have demonstrated an increased potential in the treatment and recovery of degenerative discs. Additionally, existing surgical procedures may not be suitable for IDD treatment, warranting the requirement of new regenerative therapies for the restoration of disc structure and function. In this study, a light-sensitive injectable polysaccharide composite hydrogel with excellent mechanical properties was prepared using dextrose methacrylate (DexMA) and fucoidan with inflammation-modulating properties. Through numerous in vivo experiments, it was shown that the co-culture of this composite hydrogel with interleukin-1β-stimulated NPCs was able to promote cell proliferation whilst preventing inflammation. Additionally, activation of the caveolin1-yes-associated protein (CAV1-YAP) mechanotransduction axis promoted extracellular matrix (ECM) metabolism and thus jointly promoted IVD regeneration. After injection into an IDD rat model, the composite hydrogel inhibited the local inflammatory response by inducing macrophage M2 polarization and gradually reducing the ECM degradation. In this study, we propose a fucoidan-DexMA composite hydrogel, which provides an attractive approach for IVD regeneration.

Background Epidermal growth factor receptor ( EGFR ) exon 19 insertions (19ins) represent a unique subclass of exon 19 alterations that has a relatively low frequency. Here, we aimed to elucidate the molecular characteristics and response to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in lung cancer patients with EGFR 19ins. Methods Next-generation sequencing was performed to profile the molecular characteristics of 83 non-small cell lung cancer (NSCLC) patients with EGFR 19ins. Detailed molecular profiling and efficacy analyses were performed on these patients, with comparisons to 68 EGFR 19 deletion (19del) patients. Potential resistance mechanisms were also explored. Results The prevalence of EGFR 19ins mutations was 0.17% of all the primary NSCLC patients. EGFR 19ins variants identified were I740_K745dup (86.7%) and K745_E746insVPVAIK (13.3%). Concurrent mutations frequently observed were in TP53 (50.6%), CDKN2A (12.0%), PIK3CA (10.8%), LRP1B (8.4%), and SMAD4 (8.4%). Notably, CTNNB1 was significantly associated with 19ins ( p  = 0.043). Efficacy analysis showed median progression-free survival (mPFS) for EGFR 19ins patients receiving first-line EGFR-TKI treatment was significantly shorter than for EGFR 19del patients (hazard ratio (HR) 1.98, p  = 0.005). Gefitinib was significantly less effective compared to other first-generation TKIs (HR 19.86, p  < 0.001). Furthermore, osimertinib did not generate favorable outcomes as 19dels in the first-line setting either ( p  = 0.025). Post-treatment samples revealed higher occurrences of TP53 mutations (84.6%) and presence of EGFR T790M (23.1%) at progression, with case studies highlighting osimertinib’s limited efficacy post-first-line treatment. Conclusions Comprehensive analysis of EGFR 19ins in lung cancer patients revealed genomic characteristics and clinical response, helping better inform clinical action and might facilitate the development of more precise therapeutic options for patients with these uncommon driver mutations.

Although first‐line alectinib has prolonged survival in ALK‐mutated non‐small‐cell lung cancers (NSCLCs), the response to treatment varies among patients, and the primary/early development of alectinib resistance mechanisms is still not fully understood. Here, we analyzed molecular profiles of 108 alectinib‐treated patients (first‐line and second‐line after crizotinib) with confirmed relapse by targeted sequencing of cancer‐related genes. After first‐line treatment, off‐target MET and NF2 alterations were more frequent than on‐target alterations within the first 6 months, causing primary or early resistance. Conversely, on‐target alterations became prevalent after 1 year of first‐line alectinib treatment and predominantly after second‐line. The incidence of acquired resistance also depended on EML4‐ALK variants. In variant 1 (v1), off‐target alterations were responsible for 50% of resistance cases after first‐line alectinib therapy, whereas on‐target mutations had no contribution in this subgroup. In variant 3 (v3), on‐target alterations resulted in 46% of resistance cases, whereas only 18% were caused by off‐target mutations. After second‐line treatment, the most common mutations in v1 were L1196M (42%) and G1269A (25%), while G1202R was detected in 45% of v3 tumors. These findings emphasize the importance of stratifying resistance mechanisms to guide tailored treatment for ALK‐positive NSCLCs. Alectinib resistance in ALK+ NSCLC depends on treatment sequence and EML4‐ALK variants. Variant 1 exhibited off‐target resistance after first‐line treatment, while variant 3 and later lines favored on‐target mutations. Early resistance involved off‐target alterations, like MET and NF2, while on‐target mutations emerged with prolonged therapy. Our findings provided important insights into variant‐specific strategies for the precision management of ALK‐driven NSCLC.

Clinical assessment of mediastinal and hilar lymph node involvement primarily leans on standard imaging modalities, including computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography-computed tomography (PET-CT).1 Meanwhile, invasive staging approaches, such as endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA), have demonstrated superior diagnostic effectiveness than PET-CT.2 However, considerable differences in the assessment of metastatic lymph nodes between preoperative and postoperative samples were found.3,4 Besides, while larger tumours are generally considered more closely associated with nodal metastasis in solid tumours, recent studies have shown that small adenocarcinoma tumours tend to present with lymph node metastasis.5,6 Given the unknown risk of lymph node metastasis even with small tumours, accurate pathologic determination of nodal metastasis is of great clinical importance for optimal treatment decision-making, for example, deciding the appropriate extent of lymphadenectomy for early-stage non-small cell lung cancer (NSCLC) and whether adjuvant therapy should be applied. Gene- and pathway-level enrichment analysis showed that Kelch-like ECH-associated protein 1 (KEAP1) and Protein Tyrosine Phosphatase Receptor Type B (PTPRB) mutations (p = .03 and p = .01, respectively), as well as aberrations in the NRF2 signalling pathway (p = .01), were significantly more enriched in pN-negative patients (Figure 1C). For molecular features, only chromosome 7p amplification (X7p_amp) enriched in pN-positive patients was identified as a prognostic biomarker significantly associated with OS at univariate analysis (hazard ratio [HR]: 2.1; 95% confidence interval [CI]: 1−4.2; p = .04) (Table S2). [...]several arm-level CNVs, including gains on chromosome 7q, 5p, 16p and 16q, as well as loss on chromosome 19p, exhibited a discernible difference between nodal-negative and nodal-positive patients, though the statistical power of our analysis might be affected by the limited cohort size.

Herein, we characterize the landscape and prognostic significance of the T cell receptor (TCR) repertoire of early-stage non-small cell lung cancer (NSCLC) for patients with an epidermal growth factor receptor (EGFR) mutation. β Chain TCR sequencing was used to characterize the TCR repertoires of paraffin-preserved pretreatment tumor and tumor-adjacent tissues from 57 and 44 patients with stage II/III NSCLC with an EGFR mutation treated with gefitinib or chemotherapy in the ADJUVANT-CTONG 1104 trial. The TCR diversity was significantly decreased in patients with an EGFR mutation, and patients with high TCR diversity had a favorable overall survival (OS). A total of 10 TCR Vβ-Jβ rearrangements were significantly associated with OS. Patients with a higher frequency of Vβ5-6Jβ2-1, Vβ20-1Jβ2-1, Vβ24-1Jβ2-1, and Vβ29-1Jβ2-7 had significantly longer OS. Weighted combinations of the 4 TCRs were significantly associated with OS and disease-free survival (DFS) of patients, which could further stratify the high and low TCR diversity groups. Importantly, Vβ5-6Jβ2-1, Vβ20-1Jβ2-1, and Vβ24-1Jβ2-1 had a significant relationship with gefitinib treatment, while Vβ29-1Jβ2-7 was associated with chemotherapy. Four TCR Vβ-Jβ rearrangements related to favorable OS and DFS for adjuvant gefitinib and chemotherapy in patients with an EGFR mutation with stage II/III NSCLC; this may provide a novel perspective for the adjuvant setting for resectable NSCLC.

The genomic origin and development of the biphasic lung adenosquamous carcinoma (ASC) remain inconclusive. Here, we derived potential evolutionary trajectory of ASC through whole-exome sequencing, Stereo-seq, and patient-derived xenografts. We showed that EGFR and MET activating mutations were the main drivers in ASCs. Phylogenetically, these drivers and passenger mutations found in both components were trunk clonal events, confirming monoclonal origination. Comparison of multiple lesions also revealed closer genomic distance between lymph node metastases and the ASC component with the same phenotype. However, as mutational signatures of EGFR -positive lung squamous carcinomas (LUSCs) were more comparable to EGFR -positive ASCs than to wild-type LUSCs, we postulated different origination of these LUSCs, with ASC being the potential intermediate state of driver-positive LUSCs. Spatial transcriptomic profiling inferred transformation from adenocarcinoma to squamous cell carcinoma, which was then histologically captured in vivo. Together, our results explained the development of ASC and provided insights into future clinical decisions.

Abstract The immunoregulation of tissue-engineered bone has emerged as a prominent area for bone defect repair. While this field demonstrates considerable potential, effectively managing relevant factors and maintaining a balanced immune microenvironment in practical applications remain substantial challenges that require resolution. In this study, we tested a novel comprehensive hierarchical delivery system based on the requirements of a natural immune microenvironment for inflammatory factors, to optimize local immune responses through precise regulation of drug release. Quercetin (Que)-loaded zeolite imidazolate framework-8 (ZIF-8) nanoparticles were embedded in gelatin methacrylate to create a drug-release system featuring a Zn2+ shell and quercetin core. In vivo and in vitro studies demonstrated that this dual sustained-release hydrogel-ZIF-8 system can produce low concentrations of Zn2+ at an early stage, resulting in a mild anti-inflammatory effect and proliferation of bone marrow mesenchymal stem cells. Moreover, as inflammation advances, the release of quercetin works synergistically with Zn2+ to enhance anti-inflammatory responses, reconfigure the local microenvironment, and mitigate the inflammatory response that adversely impacts bone health by inhibiting the Nuclear Factor-kappa B (NF-κB) signaling pathway, thereby promoting osteogenic differentiation. This system is pioneering for sequential microenvironment regulation based on its diverse anti-inflammatory properties, offering a novel and comprehensive strategy for bone immune regulation in the clinical treatment of bone defects. Graphical abstract