Active shimming for a 25 T NMR superconducting magnet by spectrum convergence method.

In the design of ultrahigh field nuclear magnetic resonance (NMR) superconducting magnets, it typically requires a high homogeneous magnetic field in the diameter of spherical volume (DSV) to obtain high spectrum resolution. However, shimming technique presents challenges due to the magnet bore space limitations, as accurate measurement of magnetic field distribution is very difficult, especially for customized micro-bore magnets. In this study, we introduced an active shimming method that utilized iterative adjustment of shim coil currents to improve the magnetic field homogeneity based on the full width at half maximum (FWHM) of the spectrum. The proposed method can determine the optimal set of currents for shim coils, effectively enhancing spatial field homogeneity by converging the FWHM. Experimental validation on a 25 T NMR superconducting magnet demonstrated the efficacy of the proposed method. Specifically, the active shimming method improved the field homogeneity of a 10 mm DSV from 7.09 ppm to 2.27 ppm with only four shim coils, providing a superior magnetic field environment for solid NMR and further magnetic resonance imaging (MRI) experiment. Furthermore, the proposed method can be promoted to more customized micro-bore magnets that require high magnetic field homogeneity.

Changes in effective connectivity during the visual-motor integration tasks: a preliminary f-NIRS study.

BACKGROUND: Visual-motor integration (VMI) is an essential skill in daily life. The present study aimed to use functional near-infrared spectroscopy (fNIRS) technology to explore the effective connectivity (EC) changes among brain regions during VMI activities of varying difficulty levels. METHODS: A total of 17 healthy participants were recruited for the study. Continuous Performance Test (CPT), Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A), and Beery VMI test were used to evaluate attention performance, executive function, and VMI performance. Granger causality analysis was performed for the VMI task data to obtain the EC matrix for all participants. One-way ANOVA analysis was used to identify VMI load-dependent EC values among different task difficulty levels from brain network and channel perspectives, and partial correlation analysis was used to explore the relationship between VMI load-dependent EC values and behavioral performance. RESULTS: We found that the EC values of dorsal attention network (DAN) → default mode network (DMN), DAN → ventral attention network (VAN), DAN → frontoparietal network (FPN), and DAN → somatomotor network (SMN) in the complex condition were higher than those in the simple and moderate conditions. Further channel analyses indicated that the EC values of the right superior parietal lobule (SPL) → right superior frontal gyrus (SFG), right middle occipital gyrus (MOG) → left SFG, and right MOG → right postcentral gyrus (PCG) in the complex condition were higher than those in the simple and moderate conditions. Subsequent partial correlation analysis revealed that the EC values from DAN to DMN, VAN, and SMN were positively correlated with executive function and VMI performance. Furthermore, the EC values of right MOG → left SFG and right MOG → right PCG were positively correlated with attention performance. CONCLUSIONS: The DAN is actively involved during the VMI task and thus may play a critical role in VMI processes, in which two key brain regions (right SPL, right MOG) may contribute to the EC changes in response to increasing VMI load. Meanwhile, bilateral SFG and right PCG may also be closely related to the VMI performance.

The Association of Salivary Flow Rate and Sleep Quality among Head and Neck Cancer Survivors after Radiotherapy.

BACKGROUND: Head and neck cancer survivors suffer from xerostomia and sleep disturbances after radiotherapy, both of which affect their quality of life. This study aimed to explore the role of salivary flow in the oral health and sleep quality of head and neck cancer survivors. METHODS: We recruited 120 head and neck cancer survivors who were experiencing symptoms of dry mouth or sleep disturbances post-radiotherapy from a dental clinic. We gathered their socio-demographic and clinical data, measured their salivary flow rate, and recorded their dry mouth score using the summated xerostomia inventory. Additionally, a dentist collected the DMFT (Decayed, Missing, and Filled Teeth) index. The Pittsburgh Sleep Quality Index was employed to assess their sleep quality. RESULTS: In this study, xerostomia was observed in nearly 80% of the cancer survivors. The concurrent prevalence of sleep disturbance and xerostomia was at 55%. After five years post-radiotherapy, there was a significant improvement observed in both the quality of sleep (p = 0.03) and the stimulated salivary flow rate (p = 0.04). Additionally, these improvements were noted to have commenced from the third year onwards. A significant association was found between stimulated salivary flow and dry mouth scores with poor sleep quality (p <  0.05). CONCLUSIONS: We recommend that dental professionals prioritize managing both dental and mental health issues equally for head and neck cancer survivors who have undergone radiotherapy within the past 3 years.

A gene-based score for the risk stratification of stage IA lung adenocarcinoma.

OBJECTIVE: We aim to molecularly stratify stage IA lung adenocarcinoma (LUAD) for precision medicine. METHODS: Twelve multi-institution datasets (837 cases of IA) were used to classify the high- and low-risk types (based on survival status within 5 years), and the biological differences were compared. Then, a gene-based classifying score (IA score) was trained, tested and validated by several machine learning methods. Furthermore, we estimated the significance of the IA score in the prognostic assessment, chemotherapy prediction and risk stratification of stage IA LUAD. We also developed an R package for the clinical application. The SEER database (15708 IA samples) and TCGA Pan-Cancer (1881 stage I samples) database were used to verify clinical significance. RESULTS: Compared with the low-risk group, the high-risk group of stage IA LUAD has obvious enrichment of the malignant pathway and more driver mutations and copy number variations. The effect of the IA score on the classification of high- and low-risk stage IA LUAD was much better than that of classical clinicopathological factors (training set: AUC = 0.9, validation set: AUC = 0.7). The IA score can significantly predict the prognosis of stage IA LUAD and has a prognostic effect for stage I pancancer. The IA score can effectively predict chemotherapy sensitivity and occult metastasis or invasion in stage IA LUAD. The R package IAExpSuv has a good risk probability prediction effect for both groups and single stages of IA LUAD. CONCLUSIONS: The IA score can effectively stratify the risk of stage IA LUAD, offering good assistance in precision medicine.

Cold to Hot: Tumor Immunotherapy by Promoting Vascular Normalization Based on PDGFB Nanocomposites.

Immunotherapy is a promising cancer therapeutic strategy. However, the "cold" tumor immune microenvironment (TIME), characterized by insufficient immune cell infiltration and immunosuppressive status, limits the efficacy of immunotherapy. Tumor vascular abnormalities due to defective pericyte coverage are gradually recognized as a profound determinant in "cold" TIME establishment by hindering immune cell trafficking. Recently, several vascular normalization strategies by improving pericyte coverage have been reported, whereas have unsatisfactory efficacy and high rates of resistance. Herein, a combinatorial strategy to induce tumor vasculature-targeted pericyte recruitment and zinc ion-mediated immune activation with a platelet-derived growth factor B (PDGFB)-loaded, cyclo (Arg-Gly-Asp-D-Phe-Lys)-modified zeolitic imidazolate framework 8 (PDGFB@ZIF8-RGD) nanoplatform is proposed. PDGFB@ZIF8-RGD effectively induced tumor vascular normalization, which facilitated trafficking and infiltration of immune effector cells, including natural killer (NK) cells, M1-like macrophages and CD8+ T cells, into tumor microenvironment. Simultaneously, vascular normalization promoted the accumulation of zinc ions inside tumors to trigger effector cell immune activation and effector molecule production. The synergy between these two effects endowed PDGFB@ZIF8-RGD with superior capabilities in reprogramming the "cold" TIME to a "hot" TIME, thereby initiating robust antitumor immunity and suppressing tumor growth. This combinatorial strategy for improving immune effector cell infiltration and activation is a promising paradigm for solid tumor immunotherapy.

Passive shimming for the 9.4 T whole-body MRI superconducting magnet.

A superconducting magnet with a warm-bore size of 800 mm and a center magnetic field of 9.4 T for the whole-body magnetic resonance imaging (MRI) system was developed in IEECAS, China. To achieve a highly homogeneous magnetic field over the 400 mm diameter of spherical volume (DSV), both active shimming and passive shimming techniques were employed. This paper mainly focuses on the implementation of passive shimming for the 9.4 T MRI magnet system. After four iterations, we were able to achieve peak-to-peak and root mean square field homogeneities over the DSV at 3.05 and 0.94 ppm, respectively. In addition, this paper analyzes the electromagnetic forces and system errors of passive shimming for ultra-high fields, providing valuable insights into MRI magnet engineering.

On the passive shimming of a 7 T whole-body MRI superconducting magnet: Implementation with minimized ferromagnetic materials usage and operable magnetic force control.

BACKGROUND: Magnetic field shimming of the magnet is a routine practice in a magnetic resonance imaging (MRI) system. For clinically-used 1.5 T or 3 T MRI superconducting magnets, it is generally straightforward to achieve desired magnetic field uniformity with the passive shim technique. In comparison, superconducting shims with higher shimming efficiency are usually introduced in combination with passive shimming to satisfy the higher magnetic field uniformity requirement for ultrahigh field magnets (≥7 Tesla). However, superconducting shim usually involves a complex winding structure and low-temperature environment, bringing considerable engineering challenges and extra costs in practice. PURPOSE: In this study, we aimed to improve the passive shimming method that can incorporate the unique electromagnetic properties of ultrahigh-field MRI magnets and is thus more effective for field corrections at 7T and above. METHODS: In this work, we propose a dedicated passive shimming strategy for a 7 T whole-body MRI superconducting magnet. In this method, the iron usage and magnetic force due to the iron-field interaction are strictly managed to ensure a shim tray insert is operable by manpower (without specially designed tools). RESULTS: To validate the proposed shimming strategy, a shimming experiment was implemented on a 7 T/800 mm superconducting magnet. Alternating with the odd and even shim trays in our two-round operation, the magnetic field inhomogeneity was successfully corrected from 85.36 to 7.91 ppm, achieving the magnetic field quality elevation of more than one order of magnitude. CONCLUSION: The experimental results indicated that the proposed electromagnetic technology is expected to be effective for developing ultrahigh-field MRI instruments.

Manipulation of the LiZn Alloy Process toward High-Efficiency Lithium Metal Anodes.

Synthesis of alloy-type materials (X) is one of the most effective approaches to limit lithium dendrites in Li metal anode (LMA) because of their satisfactory lithiophilicity and easy electrochemical reaction with lithium. However, current investigations have only focused on the influence of the resulting alloyed products (LiX) on the properties of LMA, but the alloying reaction process between Li+ and X has been mostly ignored. Herein, by masterly taking advantage of the alloying reaction process, a novel approach is developed to more effectively inhibit lithium dendrites than the conventional strategy that just considers the utilization of alloyed products LiX. A three-dimensional substrate material loaded with metallic Zn on the surface of Cu foam is synthesized by a simple electrodeposition process. During Li plating/stripping, both alloy reaction processes between Li+ and Zn and LiZn product are involved, which makes the disordered Li+ flux near the substrate first react with Zn metal and then results in an even Li+ concentration for more uniform Li nucleation and growth. The full cell (Li-Cu@Zn-15//LFP) exhibits the reversible capacity of 122.5 mAh g-1, and a high capacity retention of 95% is achieved after 180 cycles. This work proposes a valuable concept for the development of alloy-type materials in energy storage devices.

Development and validation of a gene-based classification model for pN2 lung adenocarcinoma.

Background: Lung adenocarcinoma (LUAD) with pathological ipsilateral mediastinal lymph node (LN) involvement (pN2) exhibits strong biological and clinical heterogeneity. Thus, it is necessary to classify the biomolecular characteristics that lead to the prognostic heterogeneity of pN2-LUAD. Methods: The clinical characteristics and bulk RNA sequencing (RNA-seq) data of 75 patients with pN2-LUAD obtained from The Cancer Genome Atlas (TCGA) database were collected as the training set. The disease-free survival (DFS) and overall survival (OS) of patients with different molecular classifications were evaluated. Next, differentially expressed genes (DEGs), biology, and immune cell infiltration in the microenvironment were analysed. Finally, DEGs in the pN2-A and pN2-B groups were included using a least absolute shrinkage and selection operator (LASSO) model, and gene signatures were selected for pN2-A/B type classification. The RNA-seq and single-nucleus RNA sequencing (snRNA-seq) data from our center (n=58) and the GSE68465 dataset (n=53) were used as the validation data sets. Results: Patients with pN2 LUAD were classified into two distinct molecular categories (pN2-A and pN2-B) based on transcriptome information, pN2-A and pN2-B represent low-risk and high-risk patients, respectively. The survival analysis showed that pN2-A patients had significantly better DFS (P=0.0162) and OS (P=0.0105) compared to pN2-B patients. Multivariate analysis confirmed that molecular classification was an independent factor affecting the prognosis of pN2 LUAD (P=0.0038, and P=0.0024). Next, we found that compared with pN2-A stage patients, pN2-B stage patients had a higher frequency of canonical oncogenic pathway mutations and enrichments. At the single-cell level, we also found that the increase of endothelial cells and the decrease of cytotoxic T/natural killer (NK) cells led to a worse prognosis for pN2-B patients compared to pN2-A patients. Moreover, we established a reasonable gene prediction model of 18 differentially expressed genes (DEGs) to classify the pN2-A and pN2-B patients. Finally, the key above-mentioned results were confirmed using our data and the GES68645 dataset. Conclusions: The molecular classification of pN2 LUAD is expected to be a powerful supplement to pN2 substaging. Driver gene status and the immune microenvironment mediate different molecular types of LUAD and provide evidence for individualized treatment strategies.

Sprouty 4 expression in human oral squamous cell carcinogenesis.

Background/purpose: Reviewing literature, sprouty 4 (SPRY4) has not been studied in human oral squamous cell carcinomas (OSCCs). The study aimed to examine SPRY4 expression in human oral squamous cell carcinogenesis. Materials and methods: A total of 95 OSCCs, 10 OPMDs with malignant transformation (MT), 17 OPMDs without MT, and six normal oral mucosa (NOM) samples were recruited for immunohistochemical staining; three OSCC tissues with normal tissue counterpart NOM were employed for Western blotting. Three human oral cancer cell lines (OCCLs), an oral precancer cell line (dysplastic oral keratinocyte, DOK), and a primary culture of normal oral keratinocytes (HOK) were used for Western blotting; OCCLs and HOK were employed for real-time quantitative reverse transcription-polymerase chain reaction. OCCLs were evaluated in terms of proliferation, migration, and invasion assays. Results: SPRY4 protein expression was significantly increased in OSCCs compared with NOM. Protein and mRNA SPRY4 expression in OCCLs were significantly elevated compared with HOK. Significant increases in the degrees of proliferation, migration, and invasion were noted in OCCLs with SPRY4 siRNA transfection compared with those without transfection. SPRY4 protein level was increased in OPMD with MT compared to OPMD without MT. SPRY4 protein was significant increase in DOK in comparison with HOK. SPRY4 protein expression was significantly increased from NOM and OPMD without MT to OSCC. SPRY4 protein expression in OCCLs was significantly enhanced compared with DOK and HOK respectively. Conclusion: Our results indicate that SPRY4 expression is possibly involved in human oral squamous cell carcinogenesis.

Efficacy of albumin-bound paclitaxel combined with nedaplatin in neoadjuvant therapy for esophageal squamous cell carcinoma: A single-center retrospective observational study.

This study was designed to observe the efficacy and safety of albumin-bound paclitaxel plus nedaplatin as neoadjuvant therapy in patients with esophageal squamous cell carcinoma (ESCC). From April 2019 to Dec 2020, patients with ESCC who underwent Mckeown surgery at our center were analyzed retrospectively. All patient received 2 to 3 cycles of albumin-bound paclitaxel combined with nedaplatin before surgery, tumor regression grade (TRG) and American National Cancer Institute Common Toxicity Criteria version 5.0 were used to evaluate its efficacy and safety. TRG grades from TRG 2 to TRG 5are considered effective in chemotherapy, TRG 1 stands for pathological complete response (pCR). A total of 41 patients were included in this study. All patients achieved R0 resection. According to the TRG classification, the number of patients assessed for TRG 1-TRG 5 were: 7 cases, 12 cases, 3 case, 12 cases and 7 cases. Its objective response rate and pCR were 82.9% (34/41) and 17.1% (7/41), respectively. We found that hematological toxicity is the most common adverse events of this regimen, with an incidence of 24.4%, followed by digestive tract reactions, with an incidence of 17.1%. Hair loss, neurotoxicity and hepatological disorder are the others, their incidence was 12.2%, 7.3%, and 2.4%; and chemotherapy related deaths were no found. Notably, 7 patients achieved pCR without recurrence or death. Survival analysis showed that patients with pCR may have longer disease-free survival (P = .085) and overall survival (P = .273), although the difference was not statistically significant. As neoadjuvant therapy for patients with ESCC, albumin-bound paclitaxel combined with nedaplatin has a higher pCR rate and less side effects. It is a reliable choice for ESCC patients as neoadjuvant therapy.

Recapitulating essential pathophysiological characteristics in lung-on-a-chip for disease studies.

Lung diseases have become a significant challenge to public healthcare worldwide, which stresses the necessity of developing effective biological models for pathophysiological and pharmacological studies of the human respiratory system. In recent years, lung-on-a-chip has been extensively developed as a potentially revolutionary respiratory model paradigm with high efficiency and improved accuracy, bridging the gap between cell culture and preclinical trials. The advantages of lung-on-a-chip technology derive from its capabilities in establishing 3D multicellular architectures and dynamic microphysiological environments. A critical issue in its development is utilizing such capabilities to recapitulate the essential components of the human respiratory system for effectively restoring physiological functions and illustrating disease progress. Here we present a review of lung-on-a-chip technology, highlighting various strategies for capturing lung physiological and pathological characteristics. The key pathophysiological characteristics of the lungs are examined, including the airways, alveoli, and alveolar septum. Accordingly, the strategies in lung-on-a-chip research to capture the essential components and functions of lungs are analyzed. Recent studies of pneumonia, lung cancer, asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis based on lung-on-a-chip are surveyed. Finally, cross-disciplinary approaches are proposed to foster the future development of lung-on-a-chip technology.

The human microbiome: A promising target for lung cancer treatment.

Lung cancer is the leading cause of cancer-related deaths worldwide, and insights into its underlying mechanisms as well as potential therapeutic strategies are urgently needed. The microbiome plays an important role in human health, and is also responsible for the initiation and progression of lung cancer through its induction of inflammatory responses and participation in immune regulation, as well as for its role in the generation of metabolic disorders and genotoxicity. Here, the distribution of human microflora along with its biological functions, the relationship between the microbiome and clinical characteristics, and the role of the microbiome in clinical treatment of lung cancer were comprehensively reviewed. This review provides a basis for the current understanding of lung cancer mechanisms with a focus on the microbiome, and contributes to future decisions on treatment management.

Overexpression of transient receptor potential melastatin 6 during human oral squamous cell carcinogenesis.

Background/purpose: Transient receptor potential melastatin (TRPM) channel is involved in cell proliferation and cell survival. Eight members (TRPM1-8) are within the TRPM subfamily. The current study is aimed to investigate TRPM6 expression in human oral carcinogenesis. Materials and methods: Sixty-six oral squamous cell carcinomas (OSCCs), 47 oral potentially malignant disorders (OPMD) with moderate-severe epithelial dysplasia (ED), 28 OPMD with mild ED, and 33 normal oral mucosa (NOM) samples were subjected to immunohistochemical staining. Two human oral cancer cell lines (OCCLs), an oral premalignant cell line (DOK), and a normal oral keratinocyte culture (HOK) were used for Western blot analysis. OCCLs were evaluated for proliferation, migration, invasion assays, and intracellular calcium concentration. Results: TRPM6 protein expression in OSCC was significantly increased as compared with normal samples. Protein expression of TRPM6 in OCCLs was significantly higher as compared with HOK. Significant decreases in degrees of proliferation, migration, invasion, and intracellular calcium concentration were noted in OCCLs with TRPM6 siRNA transfection as compared with those without transfection. Significantly increased TRPM6 protein level was noted in OPMD with moderate-severe ED as compared with those with mild ED. Conclusion: Our results implicate that TRPM6 overexpression is potentially related to human oral carcinogenesis.

Carbonized Polymer Dots with Controllable N, O Functional Groups as Electrolyte Additives to Achieve Stable Li Metal Batteries.

Electrolyte additive is an effective strategy to inhibit the uncontrolled growth of Li dendrites for lithium metal batteries (LMBs). However, most of the additives are complex synthesis and prone to decompose in cycling. Herein, in order to guide the homogeneous deposition of Li+ , carbonized polymer dots (CPDs) as electrolyte additives are successfully designed and synthesized by microwave (M-CPDs) and hydrothermal (H-CPDs) approaches. The controllable functional groups containing N or O (especially pyridinic-N, pyrrolic-N, and carboxyl group) enable CPDs to keep stable in electrolytes for at least 3 months. Meanwhile, the clusters formed between CPDs and Li+ through electrostatic interaction effectively guide the uniform Li dispersion and limit the "tip effect" and dendrite formation. Moreover, as lithiophilic groups increase, the strong electrostatic interference for the solvation effect of Li+ in the electrolyte is formed, which induces faster Li+ diffusion/transfer. As expected, H-CPDs achieve the ultra-even Li+ transfer. The corresponding Li//LiFePO4 full cell delivers a high capacity retention rate of 93.8% after 200 cycles, which is much higher than that of the cells without additives (61.2%) and with M-CPDs (83.7%) as additives. The strategy in this work provides a theoretical direction for CPDs as electrolyte additives used in energy storage devices.

Relationships between sensory integration and the core symptoms of attention-deficit/hyperactivity disorder: the mediating effect of executive function.

Attention-deficit/hyperactivity disorder (ADHD) is often accompanied by executive function deficits and functional alterations in sensory integration. The present study aimed to investigate the relationship between ADHD core symptoms, executive function, and sensory integration in children with ADHD. A total of 228 children with ADHD were recruited for our study. The Sensory Organization Test (SOT) and Child Sensory Integration Scale (CSIS) evaluated the sensory integration ability from lab-based and scaled-based perspectives, respectively. Three core components of executive functions (inhibition, working memory, and set-shifting) were assessed using both lab-based tests and the relevant factors from the behavior rating inventory of executive function (BRIEF). Partial correlation analysis was performed to explore the correlation of sensory integration with EF and ADHD core symptoms. Based on the observed significant correlation, bootstrap analyses were further conducted to explore the potential mediating effect of EF on the relationship between sensory integration and ADHD core symptoms. ADHD symptoms and EF were significantly correlated with CSIS scores; no factors were significantly correlated with SOT performance. In detail, the vestibular-balance score was negatively correlated with both inattention and hyperactivity/impulsivity symptoms, while the hyper-sensory and proprioception scores were negatively correlated with only inattention symptoms. For the scaled-based EF, vestibular-balance was negatively correlated with inhibition and working memory, and the hyper-sensory score was negatively correlated with shift factor. No correlation was found for the lab-based EF tests. The subsequent mediation analysis found that inhibition partially mediated the relationship between vestibular balance and hyperactivity/impulsivity symptoms. Working memory completely mediated the relationship between vestibular-balance, hyper-sensory, proprioception, and inattention symptoms. These results were well validated in an independent sample. Our present findings demonstrated that the functional alteration in basic sensory integration might be associated with impairments of executive functions and then lead to the behavioral expression of ADHD. The present findings might provide a new perspective to understand the occurrence of ADHD symptoms and potential precise intervention methods.

Heterogeneity and Clinical Effect of Epidermal Growth Factor Receptor in Primary Lung and Brain Metastases of Nonsmall Cell Lung Cancer.

INTRODUCTION: This study aimed to analyze the heterogeneity in epidermal growth factor receptor (EGFR) gene mutation and its impact on clinical outcomes in primary tumor and corresponding brain metastasis (BM) in nonsmall cell lung cancer (NSCLC). MATERIALS AND METHODS: Primary pulmonary tumors and paired BMs of 27 NSCLC patients were surgically removed. All brain lesions were histologically confirmed as metastatic NSCLC. EGFR gene mutation status was detected by using amplification refraction mutation system. McNemar test was performed to compare EGFR mutation status between lung primary tumors and metastatic brain tumors and Kappa test was performed to quantify the agreement between the two. RESULTS: Of the 27 patients, nine cases were found to have EGFR mutations in BMs and 10 had a positive EGFR mutation status in primary lung tumor tissue. The rate of consistency of the matched tumor was 24/27 (88.9%). Among the three cases presenting EGFR mutational heterogeneity, two patients harbored an EGFR mutation in the primary tumor but not in the BMs; meanwhile, the last patient demonstrated the opposite pattern. Compared to patients with consistent EGFR mutations, patients with inconsistent mutations showed better outcomes. Further analysis revealed that the two patients whose EGFR mutant-type primary tumor progressed to wild-type cerebral metastatic tumor had longer overall survival than the patient whose EGFR wild-type primary tumor progressed to mutant-type brain metastatic tumor. CONCLUSIONS: Heterogeneity of EGFR mutation status was observed between primary NSCLC and paired BM. Patients possessing a wild-type EGFR mutation in BM might have better outcomes, especially those with transition from mutant to wild-type.

Evolution of lung adenocarcinoma from preneoplasia to invasive adenocarcinoma.

OBJECTIVE: Mutations in driver genes contribute to the development and progression of lung adenocarcinoma (LUAD). However, in the dynamic evolutionary process from adenocarcinoma in situ (AIS) to minimally invasive adenocarcinoma (MIA) and eventually to invasive adenocarcinoma (IAC), the role of driver genes is currently unclear. This study aimed to analyse the role of driver gene status in the progression of LUAD from preneoplasia to IAC. METHODS: Patients with LUAD who underwent surgery in our centre from March 2015 to December 2019 were retrospectively analysed, and LUAD patients with tumour sizes ≤3.0 cm and pN0 were included in the final analysis. The mutation status of common driver genes, including EGFR, ALK and ROS1, was detected. According to the pathological characteristics, the patients were divided into three stages: AIS, MIA and IAC. We analysed the distribution of driver gene mutation frequencies across three stages of LUAD. In addition, we performed univariate and multivariate analyses of IAC patients to screen for relevant variables (driver genes and clinicopathological features) affecting their prognosis. RESULTS: Ultimately, 759 patients with LUAD were enrolled, including 135, 130, and 494 cases of AIS, MIA, and IAC, respectively. EGFR mutations were identified in 359 (61.8%) patients, and with the transition from AIS to MIA, the frequency of EGFR mutations increased from 33.3% to 50.8%, p = 0.004, whereas the frequency of EGFR mutations was comparable for MIA and IAC (50.8% vs. 50.2%, p = 0.922). Moreover, ALK and ROS1 gene fusions were identified in 17 cases (2.2%) and 2 cases (3.0‰) respectively. For AIS, neither ALK gene nor ROS1 gene fusions were observed. When the tumour progressed to MIA, the ALK fusion frequency was 2.3% (3/130), which was basically consistent with the ALK fusion frequency of 2.8% in IAC, p = 0.143. For IAC, fusions of ROS1 fell into this category. In addition, we found that 40 patients (5.3%) developed metastasis/recurrence, and 14 patients (1.8%) died of cancer-specific related diseases. Notably, for AIS, there were no recurrences and no deaths, and for MIA, only 1 patient died with LUAD. Finally, survival analysis was performed in patients with stage IA invasive adenocarcinoma, and EGFR-mutant patients showed better DFS than EGFR-wild-type patients (p = 0.036). Conversely, patients with ALK fusions showed worse DFS than those with ALK wild-type (p = 0.004), and the same results were found in OS analysis. CONCLUSIONS: The accumulation of EGFR driver gene mutation frequencies mediates the progression of LUAD from AIS to MIA. When the tumour progresses to stage IA invasive adenocarcinoma, multivariate analysis based on driver gene status can be used as a pivotal prognostic factor.

Delineating the dynamic evolution from preneoplasia to invasive lung adenocarcinoma by integrating single-cell RNA sequencing and spatial transcriptomics.

The cell ecology and spatial niche implicated in the dynamic and sequential process of lung adenocarcinoma (LUAD) from adenocarcinoma in situ (AIS) to minimally invasive adenocarcinoma (MIA) and subsequent invasive adenocarcinoma (IAC) have not yet been elucidated. Here, we performed an integrative analysis of single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) to characterize the cell atlas of the invasion trajectory of LUAD. We found that the UBE2C + cancer cell subpopulation constantly increased during the invasive process of LUAD with remarkable elevation in IAC, and its spatial distribution was in the peripheral cancer region of the IAC, representing a more malignant phenotype. Furthermore, analysis of the TME cell type subpopulation showed a constant decrease in mast cells, monocytes, and lymphatic endothelial cells, which were implicated in the whole process of invasive LUAD, accompanied by an increase in NK cells and MALT B cells from AIS to MIA and an increase in Tregs and secretory B cells from MIA to IAC. Notably, for AIS, cancer cells, NK cells, and mast cells were colocalized in the cancer region; however, for IAC, Tregs colocalized with cancer cells. Finally, communication and interaction between cancer cells and TME cell-induced constitutive activation of TGF-ß signaling were involved in the invasion of IAC. Therefore, our results reveal the specific cellular information and spatial architecture of cancer cells and TME subpopulations, as well as the cellular interaction between them, which will facilitate the identification and development of precision medicine in the invasive process of LUAD from AIS to IAC.