Esophageal squamous cell carcinoma (ESCC) lacks a standardized classification system, resulting in inconsistent clinical management and a suboptimal prognosis. This study addresses the urgent need for a robust consensus taxonomy to facilitate precision treatment for ESCC. We employed a network-based approach to elucidate the interconnections among eight existing classification systems, leading to the identification of four distinct consensus molecular subtypes (ECMSs): ECMS1-MET (metabolic), characterized by dysregulated metabolic pathways and NFE2L2 activation; ECMS2-CLS (classical), featuring upregulated cell cycle and canonical signaling pathways; ECMS3-IM (immunomodulatory), marked by robust immune activation and elevated PD-1 expression; and ECMS4-MES (mesenchymal), associated with mesenchymal transition, stromal activation, and VEGF signaling. To improve clinical applicability, we developed an image-based framework (imECMS) that utilizes spatial organization features (SOFs) quantified from autodelineated hematoxylin‒eosin (H&E)-stained whole-slide images through deep learning algorithms. The imECMS classifier assigns patients to one of the four ECMS subtypes, which correlate with distinct molecular characteristics, prognoses, and responses to neoadjuvant chemotherapy and immunotherapy. Validation across multiple independent cohorts confirmed that the imECMS accurately classifies ESCC subtypes from histopathological images, offering a robust and effective tool for precision medicine. In summary, the ECMS/imECMS subtyping systems we developed are the most robust frameworks for ESCC to date, providing clear biological insights and a foundation for clinical stratification and targeted therapies.

The exon 19 deletion (19 Del) and the exon 21 L858R point mutation (21 L858R) are two main subtypes of EGFR-mutant lung adenocarcinoma (LUAD) with distinct response to targeted treatment and immunotherapy. Understanding the intratumor heterogeneity (ITH) of EGFR-mutant LUAD may explain the reason. 157 multi-region tumor samples and matched distant normal lung tissues from 29 treatment-naïve operable EGFR-mutant LUAD patients were collected to perform whole genome sequencing, panel sequencing and whole transcriptome sequencing. We aimed to comprehensively assess genomic and transcriptomic ITH between 19 Del and 21 L858R. The 21 L858R LUAD exhibited significantly higher copy number variation (CNV) ITH index (ITHi) compared to the 19 Del LUAD, but there was no significant difference in somatic single-nucleotide variant (SNV) ITHi between them. Meanwhile, 19 Del LUAD owned more clonal genetic alterations, while 21 L858R LUAD had more subclonal events. Both linear and branch evolution models existed in 19 Del and 21 L858R LUAD. Besides, 19 Del seemed to be more dominant for driving tumor development, while other driver mutations participated jointly with 21 L858R in tumor evolution. Moreover, 19 Del LUAD exhibited significantly higher immune score and checkpoint inhibition signature than 21 L858R. Additionally, it indicated that high-level TMB might be a favorable prognostic factor for EGFR-mutant LUAD. Our study demonstrated diverse genomic heterogeneity and tumor immune microenvironment in EGFR-mutant LUAD, which might elaborate on potential explanations for different efficacy between 19 Del and 21 L858R and provide valuable hints to treatment strategy.

Objectives To evaluate whether bilateral mediastinal lymphadenectomy (BML) affects the feasibility and invasiveness of lung resection in patients with lung cancer and its associated risks of adverse effects (AE). Methods This multicentre randomized trial compared BML and systematic lymph node dissection (SLND). In all patients, standard anatomical lung resection was performed. In the BML group, the contralateral mediastinum was additionally dissected using the cervical approach. Results In total, 279 patients (135 BML and 144 SLND) were eligible for analysis; both groups had comparable basic clinical parameters. Both groups were comparable in terms of resection type (P = 0.193), blood loss (P = 0.927), and number of AE (P = 0.289). Compared with the SLND group, the BML group had a longer duration of surgery (440 minutes vs 133 minutes, P < 0.001) and a greater number of removed lymph nodes (45 vs 21, P < 0.001). Both groups were comparable in terms of AE (P = 0.171) and severe AE (P = 0.179). In the BML group, chest drainage duration and air leak duration were longer (8.3 vs 4.5 days, P < 0.001 and 1.9 vs 1.5 days, P = 0.026, respectively), the total volume of chest tube discharge was larger (1573 vs 907 mL, P < 0.001), and pain intensity on each of the 5 postoperative days was higher (P < 0.001). Conclusions BML during pulmonary resection in patients with lung cancer is feasible and does not increase the risk of complications. It enables significantly more extensive lymphadenectomy but is associated with a longer duration of surgery and increased air leak duration, chest tube drainage, and pain intensity.

Relative timing of mutations in the coding regions of genes in the pathway.

Background & Aims:Patient-derived tumor organoids (PDTOs) are a reliable model for preclinical and translational studies. Despite positive retrospective correlations with patient response, challenges such as culture success, cost, standardization, and time constraints hinder their clinical utility in precision medicine. Here, we optimize PDTO establishment using growth factor-reduced media (GF-) to mitigate these challenges and (1) identify somatic variant indicators that can improve the therapeutic index of existing FDA-approved drugs against hepatocellular carcinoma (HCC), (2) elucidate synthetic lethal candidates against undruggable HCC driver mutations, and (3) assess the feasibility of PDTOs in personalized therapy. Methods:We successfully established a panel of 23 PDTOs from patients with HCC undergoing curative hepatectomy using a protocol primarily based on growth factor-reduced medium. PDTOs were subjected to comprehensive analyses, including the identification of hallmark mutations, assessment of genomic heterogeneity, transcriptomic profiling, and histological characterization. A 100-drug repurposing screen was conducted on the PDTOs and organoids derived from adjacent non-tumoral and normal livers to explore tumor-specific drug responses. Pharmacogenomic analysis using elastic net was performed (cut-off p <0.05) and synthetic lethality links were subject to experimental validation. The clinical relevance of PDTOs in personalized therapy were investigated through two case studies. Results:Our results reveal that GF-derived PDTOs mimic histology and genetic heterogeneity of HCC. Pharmacogenomic analysis showed that the majority of tested FDA-approved drugs were not associated with HCC driver mutations (<5%). In addition, non-canonical signaling from CTNNB1 mutations were associated with ceritinib sensitivity (p <0.0001) via polypharmacological targeting of RPS6KA3. The PDTO case study showed clear benefit to patient survival by aiding clinical management. Conclusions:Our findings underscore the utility of PDTOs established from minimal GF media in many facets of precision oncology advancements. Impact and implications:Patient-derived tumor organoids are a reliable model for preclinical and translational studies. Despite positive retrospective correlations with patient response data, challenges such as culture success, cost, standardization, and time constraints hinder their clinical utility in guiding precision medicine. This study underscores the utility of patient-derived organoids established from growth factor-reduced media in many facets of precision oncology, showing for the first time in hepatocellular carcinoma, clear benefit to patient survival in a proof-of-concept case study.

This study aimed to investigate the correlations between short- and long-term efficacy of immune checkpoint inhibitors (ICIs) and pretreatment laboratory/imaging parameters in advanced non-small cell lung cancer (NSCLC), and to construct risk prediction models. We enrolled 137 NSCLC patients with stage IIIB-IV disease who completed 4 cycles of PD-1/PD-L1 inhibitor monotherapy or combination therapy. All participants underwent pretreatment laboratory assessments encompassing inflammatory markers, lymphocyte subsets, tumor biomarkers, coagulation profiles, and contrast-enhanced computed tomography (CE-CT) scans. The primary endpoints were objective response rate (ORR) and overall survival (OS), with progression-free survival (PFS) as the secondary endpoint. Univariate and multivariate logistic regression analyses were performed to identify significant predictors of short-term treatment response and develop an efficacy prediction model. For long-term outcomes, univariate and multivariate Cox proportional hazards regression analyses were conducted to establish a prognostic risk model. The final models were presented as nomograms and validated through receiver operating characteristic (ROC) curve analysis, calibration curves, and decision curve analysis (DCA). CD4(+) T-cell count (P = .007), fibrinogen (FIB, P = .047), and mediastinal lymph node enlargement (P = .028) emerged as independent predictors of ORR. The prediction model demonstrated an area under the ROC curve (AUC) of 0.838, with bootstrap validation (1000 resamples) yielding a mean AUC of 0.867. Calibration analysis, DCA, and clinical impact curve (CIC) collectively confirmed the model's robust predictive performance. For OS, metastatic site (P = .007), neutrophil-to-lymphocyte ratio (NLR, P = .025), carbohydrate antigen 125 (CA125, P = .020), cytokeratin 19 fragment (CYFRA 21-1, P = .004), FIB (P < .001), and pleural effusion (P < .001) were identified as significant prognostic determinants. The model achieved AUC values of 0.858 and 0.860 for 1- and 2-year survival prediction, respectively. Calibration plots revealed excellent concordance between predicted and observed survival probabilities at both timepoints. Furthermore, DCA indicated superior net clinical benefit of the prognostic model compared to random chance models across threshold probability ranges. Comprehensive prediction models integrating clinical characteristics, laboratory biomarkers, and imaging parameters were developed for both short- and long-term efficacy evaluation of immunotherapy, offering clinically actionable guidance for personalizing treatment strategies in advanced NSCLC.

PURPOSE:Immunotherapy has transformed the neoadjuvant treatment landscape for patients with resectable locally advanced non-small cell lung cancer (NSCLC). However, a population of patients cannot obtain major pathologic response (MPR) and thus benefit less from neoadjuvant immunotherapy, highlighting the need to uncover the underlying mechanisms driving resistance to immunotherapy. METHODS:Two published single-cell RNA sequencing (scRNA-seq) datasets were used to analyze the subsets of cancer-associated fibroblasts (CAFs) and T cells and functional alterations after neoadjuvant immunotherapy. The stromal signature predicting ICI response was identified and validated using our local cohort with stage III NSCLC receiving neoadjuvant immunotherapy and other 4 public ICI transcriptomic cohorts. RESULTS:Non-MPR tumors showed higher enrichment of CAFs and increased extracellular matrix deposition than MPR tumors, as suggested by bioinformatic analysis. Further, CAF-mediated immune suppression may involve reciprocal interactions with T cells in addition to a physical barrier mechanism. In contrast, MPR tumors demonstrated therapy-induced activation of memory CD8+ T cells into an effector phenotype. Additionally, neoadjuvant immunotherapy resulted in expansion of precursor exhausted T (Texp) cells, which were remodeled into an anti-tumor phenotype. Notably, we identified metabolic heterogeneity within distinct T cell clusters during immunotherapy. Methionine recycling emerged as a predictive factor for T-cell differentiation and a favorable pathological response. The stromal signature was associated with ICI response, and this association was validated in five independent ICI transcriptomic cohorts. CONCLUSION:These discoveries underscore the distinct tumor microenvironments in MPR and non-MPR patients and may elucidate resistance mechanisms to immunotherapy in NSCLC.

Cancer-associated fibroblasts (CAF) are pivotal constituents of the tumor microenvironment that significantly influence cancer aggressiveness through the secretion of various factors. A more detailed characterization of the specific secretions exclusive to CAFs that drive tumor progression could identify potential targets to perturb this intracellular cross-talk. In this study, we identified latent TGFβ-binding protein 2 (LTBP2) as a unique protein secreted exclusively by esophageal squamous cell carcinoma (ESCC) CAFs that promotes metastasis and chemoresistance. LTBP2 exerted its oncogenic effects by interacting with integrin α6β4, which serves as a functional receptor, and thereby activating Src signaling in ESCC cells. Notably, targeting LTBP2 with specific antagonistic antibodies markedly increased the susceptibility of ESCC cells to chemotherapeutic agents. These findings highlight the pivotal role of LTBP2 as a crucial mediator of CAF-induced cancer cell aggression and introduce it as a promising target to enhance chemotherapeutic efficacy in ESCC. SIGNIFICANCE:CAF-secreted LTBP2 binds integrin α6β4 and activates Src signaling to drive metastasis and chemoresistance in esophageal cancer, highlighting LTBP2 as a key regulator of CAF-mediated tumor progression that can be therapeutically targeted.

Molecular targeted therapy has revolutionized the clinical practice for various cancer patients. The therapeutic benefits vary greatly due to low bioavailability, insufficient accessibility on targets, and presence of intrinsic and acquired resistance. Restrained by additional blood-brain barrier (BBB), treatments of small molecule inhibitors in brain tumors have made less progress. Here, we find that ApoE peptide-decorated nanomicelles (ApoE-PM) based on phenylboronic acid-functionalized polypeptide mediate efficient co-delivery of polo-like kinase 1 (PLK1) and B-cell lymphoma-2/xL (BCL-2/xL) inhibitors to brain tumor. Nanomicelles exhibit exceptional stability, proportional co-loading and responsive release of small molecule inhibitors with diverse properties and molecular targets, by exploiting the B-N coordination and it-it stacking between phenylboronic acid groups and drugs. Notably, micelles decorated with ApoE peptide on the surface and loaded with volasertib and navitoclax at a weight ratio of 1/1 (ApoE-PMVN) reveals proficient BBB crossing, efficient internalization and strong synergistic antiproliferation effect in GL261 cells. In mice bearing orthotopic GL261 glioblastoma (GBM) model, ApoEPMVN affords significant growth inhibition and markedly improved survival time via synergistic inhibition of PLK1, BCL-2/xL and myeloid cell leukemia 1 (MCL-1) targets. PM provides a versatile strategy for co-delivery of small molecule inhibitors, offering a potential for synergistic therapy of brain tumors.

The quality control and filtration of cancer somatic mutations (CAMs), including the elimination of false positives due to technical bias and the selection of key mutation candidates, are crucial steps for downstream analysis in cancer genomics. However, due to diverse needs and the lack of standardized filtering criteria, the filtering strategies applied vary from study to study, often resulting in reduced efficiency, accuracy, and reproducibility. Here, we present CaMutQC, a heuristic quality control and soft-filtering R/Bioconductor package designed specifically for CAMs. CaMutQC enables users to remove false positive mutations, select potential mutation candidates, and estimate Tumor Mutation Burden (TMB) with a single line of code, using either default or customized parameters. A filter report and a code log can also be generated after the filtration process to facilitate reproducibility and comparison. The application of CaMutQC to a Whole-exome Sequencing (WES) benchmark dataset demonstrated its strong capability by eliminating 85.55 % of false positive Single nucleotide variants (SNVs) while retaining 90.72 % of true positive SNVs. Additionally, an additional 11.56 % of true positive SNVs were rescued through CaMutQC's built-in union strategy. Similar results were observed for Insertions and Deletions (INDELs). CaMutQC is freely available through Bioconductor at https://bioconductor.org/packages/CaMutQC/ under the GPL v3 license.

Visible light-based positioning (VLP) is indispensable for integrated sensing and communication in optical wireless networks. Conventional VLP methods require an accurate Lambertian emission model (LEM) with fixed parameters. However, this is hard to be met in practice due to inevitable measurement errors, and thus a small LEM error will lead to serious VLP performance loss. To solve this issue, a joint LEM calibration and positioning (JCAP) scheme is proposed. As the JCAP problem is non-convex in nature, a majorization minimization-based joint optimization method is developed to exploit hidden-convex substructures of system models, thus yielding a tractable JCAP scheme. Moreover, the impact of system parameters (e.g., carrier frequency, initial LEM error and noise) on the VLP performance is revealed, which is useful for efficient VLP network development. It is verified by simulations that the proposed JCAP method outperforms the state-of-the-art VLP baselines due to our problem-specific joint LEM calibration mechanism design.

Summary: Deficiency of DNA repair pathways drives the development of colorectal cancer. However, the role of the base excision repair (BER) pathway in colorectal cancer initiation remains unclear. This study shows that Nei-like DNA glycosylase 1 (NEIL1) is highly expressed in colorectal cancer (CRC) tissues and associated with poorer clinical outcomes. Knocking out neil1 in mice markedly suppresses tumorigenesis and enhances infiltration of CD8+ T cells in intestinal tumors. Furthermore, NEIL1 directly forms a complex with SATB2/c-Myc to enhance the transcription of COL17A1 and subsequently promotes the production of immunosuppressive cytokines in CRC cells. A NEIL1 peptide suppresses intestinal tumorigenesis in ApcMin/+ mice, and targeting NEIL1 demonstrates a synergistic suppressive effect on tumor growth when combined with a nuclear factor κB (NF-κB) inhibitor. These results suggest that combined targeting of NEIL1 and NF-κB may represent a promising strategy for CRC therapy.

Visible light-based positioning (VLP) of user device (UD) is important for integrated visible light communication (VLC) and sensing, which however seriously suffers from scattering interference. In this paper, a novel orthogonal-frequency-division-multiplexing (OFDM)-enabled scattering interference mitigation (SIM) method is proposed to address this issue. The proposed OFDM-enabled SIM method will jointly detect the UD location and scattering channel state, and hence scattering interference to VLP will be alleviated via channel equalization. It is corroborated by simulations that our VLP method enhanced by the proposed OFDM-based SIM approach outperforms state-of-the-art VLP baseline methods, due to the cross-domain cooperation between “OFDM-based VLC” and “location detection”.

Supplementary Table 1. Representativeness of Study Participants

Supplementary Figure 4. Results of univariate analyses for progression-free survival

Based on the time series online prediction model, this paper proposes a WE-OSELM online prediction algorithm, which can control the product life and performance in real time in the field of engine, and effectively manage huge system engineering. The prediction model is closely related to the actual application of system engineering product modules and has great operability. This paper proposes the IPW-OSELM algorithm and error compensation algorithm with information perception weight as the core point, and relies on a dual parallel single hidden layer feedforward neural network to efficiently integrate related algorithms to form a WE-OSLEM algorithm. Among them, the information perception weight clarifies the relationship between point similarity and regional similarity in the case of fluctuations in the effectiveness of the data characteristics of the prediction object or mutations in a limited range, so that the online prediction algorithm has a more acute data characteristic perception ability in the process of responding to changes in data characteristics.

Abstract A compact decoupling microstrip antenna array with high isolation by using two methods, including SRR branches and SRR slots, is proposed, whose adjacent unit’s center-to-center distance is 0.35λ. Parasitic patches and air cavities are introduced to achieve broadband characteristics of antenna elements. Spatial coupling is reduced by loading SRR (Split-ring resonator) branches between two feeding elements. Moreover, surface current coupling on the floor can be blocked by SRR slots etched on the floor. Simulated and measured results reveal that the designed antenna impedance bandwidth covers 6.7GHz ~ 8.7GHz (26%). The isolation within the working frequency band is better than 22dB. The prototype of the proposed antenna is easy to fabricate, which provides a feasible solution for achieving high isolation between multiple antennas in engineering.

Supplementary Table 8. Associations of genetic alterations with prognosis.

BACKGROUND AND OBJECTIVE:To investigate the oncologic outcomes of patients with esophageal squamous cell carcinoma (ESCC) who have achieved a pathologic complete response (pCR) of the primary tumor (ypT0) after neoadjuvant chemoradiotherapy (NCRT). METHODS:Patients with thoracic ESCC who underwent scheduled NCRT followed by surgery at our hospital between January 2010 and December 2022 were retrospectively analyzed. Only patients with ypT0 disease were enrolled in this study. RESULTS:A total of 118 patients were ultimately enrolled in this study. Ninety-two patients achieved pCR in the primary tumor and lymph nodes (ypT0N0), while 26 patients had residual metastatic disease in 52 lymph nodes (ypT0N+). Forty-five of the 52 lymph nodes with residual tumors were abdominal lymph nodes. Positive lymph nodes were more often observed in patients with tumors located in the lower third of the esophagus. The 1-, 3-, and 5-year overall survival (OS) rates for the entire study group were 96.5%, 79.5%, and 77.1%, and the 1-, 3-, and 5-year disease-free survival (DFS) rates were 90.5%, 76.8%, and 69.0%, respectively. According to multivariate analyses, pN classification was an independent predictor of both OS and DFS (P < 0.05), while sex and cT classification were also found to be independent prognostic factors for DFS (P < 0.05). CONCLUSIONS:Residual nodal metastatic disease in patients with ypT0 ESCC after NCRT was more often found in the abdominal lymph nodes. pN classification was an independent predictor of both OS and DFS for ypT0 ESCC patients after NCRT.