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Abstract Background Gastric cancer (GC) is one of the deadliest malignant tumors with unknown pathogenesis. Due to its treatment resistance, high recurrence rate, and lack of reliable early detection techniques, a majority of patients have a poor prognosis. Therefore, identifying new tumor biomarkers and therapeutic targets is essential. This review aims to provide fresh insights into enhancing the prognosis of patients with GC by summarizing the processes through which microRNAs (miRNAs) regulate the tumor microenvironment (TME) and highlighting their critical role in the TME. Main text A comprehensive literature review was conducted by focusing on the interactions among tumor cells, extracellular matrix, blood vessels, cancer-associated fibroblasts, and immune cells within the GC TME. The role of noncoding RNAs, known as miRNAs, in modulating the TME through various signaling pathways, cytokines, growth factors, and exosomes was specifically examined. Tumor formation, metastasis, and therapy in GC are significantly influenced by interactions within the TME. miRNAs regulate tumor progression by modulating these interactions through multiple signaling pathways, cytokines, growth factors, and exosomes. Dysregulation of miRNAs affects critical cellular processes such as cell proliferation, differentiation, angiogenesis, metastasis, and treatment resistance, contributing to the pathogenesis of GC. Conclusions miRNAs play a crucial role in the regulation of the GC TME, influencing tumor progression and patient prognosis. By understanding the mechanisms through which miRNAs control the TME, potential biomarkers and therapeutic targets can be identified to improve the prognosis of patients with GC.

Although multidisciplinary team (MDT) diagnosis and treatment model can improve the quality of life and survival prognosis of the patients, why does it not reach the expected goal of the MDT diagnosis and treatment model? The main reason is that the diagnosis and treatment mode of MDT in lung cancer lags behind the progress of various treatment methods. By analyzing the latest research results of MDT diagnosis and treatment of lung cancer at home and abroad, combined with the experience of MDT diagnosis and treatment of lung cancer in the Lung Cancer Center of West China Hospital of Sichuan University, this article will discuss and summarize the progress and future direction of MDT in lung cancer from the following aspects: (1) The connotation and extension of MDT diagnosis and treatment mode of lung cancer need to be changed and adapted to new methods of diagnosis and treatment; (2) The clinical decision making in the diagnosis and treatment of MDT in lung cancer should be transformed from "multidisciplinary consultation (MDC)" to "MDT"; (3) The diagnosis and treatment process of MDT in lung cancer should shift from "fire brigade mode" to "firewall mode", and finally implement "individualized whole-process management mode"; (4) The path of MDT diagnosis and treatment of lung cancer should be changed from "temporary convening mode" to "single disease center system mode of lung cancer".

Abstract Background Volatile organic compounds (VOCs) encompass hundreds of high production volume chemicals and have been reported to be associated with adverse respiratory outcomes such as chronic obstructive pulmonary disease (COPD). However, research on the combined toxic effects of exposure to various VOCs on COPD is lacking. We aimed to assess the effect of VOC metabolite mixture on COPD risk in a large population sample. Methods We assessed the effect of VOC metabolite mixture on COPD risk in 5997 adults from the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2020 (pre-pandemic) using multivariate logistic regression, Bayesian weighted quantile sum regression (BWQS), quantile-based g-Computation method (Qgcomp), and Bayesian kernel machine regression (BKMR). We explored whether these associations were mediated by white blood cell (WBC) count and total bilirubin. Results In the logistic regression model, we observed a significantly increased risk of COPD associated with 9 VOC metabolites. Conversely, N-acetyl-S-(benzyl)-L-cysteine (BMA) and N-acetyl-S-(n-propyl)-L-cysteine (BPMA) showed insignificant negative correlations with COPD risk. The overall mixture exposure demonstrated a significant positive relationship with COPD in both the BWQS model (adjusted odds ratio (OR) = 1.30, 95% confidence interval (CI): 1.06, 1.58) and BKMR model, and with marginal significance in the Qgcomp model (adjusted OR = 1.22, 95% CI: 0.98, 1.52). All three models indicated a significant effect of the VOC metabolite mixture on COPD in non-current smokers. WBC count mediated 7.1% of the VOC mixture associated-COPD in non-current smokers. Conclusions Our findings provide novel evidence suggesting that VOCs may have adverse associations with COPD in the general population, with N, N- Dimethylformamide and 1,3-Butadiene contributing most. These findings underscore the significance of understanding the potential health risks associated with VOC mixture and emphasize the need for targeted interventions to mitigate the adverse effects on COPD risk.

Abstract. Liver metastases (LMs) are common in lung cancer. Despite substantial advances in diagnosis and treatment, the survival rate of patients with LM remains low as the immune-suppressive microenvironment of the liver allows tumor cells to evade the immune system. The impact of LMs on the outcomes of immune checkpoint inhibitors in patients with solid tumors has been the main focus of recent translational and clinical research. Growing evidence indicates that the hepatic microenvironment delivers paracrine and autocrine signals from non-parenchymal and parenchymal cells. Overall, these microenvironments create pre- and post-metastatic conditions for the progression of LMs. Herein, we reviewed the epidemiology, physiology, pathology and immunology, of LMs associated with non-small cell lung cancer and the role and potential targets of the liver microenvironment in LM in each phase of metastasis. Additionally, we reviewed the current treatment strategies and challenges that should be overcome in preclinical and clinical investigations. These approaches target liver elements as the basis for future clinical trials, including combinatorial interventions reported to resolve hepatic immune suppression, such as immunotherapy plus chemotherapy, immunotherapy plus radiotherapy, immunotherapy plus anti-angiogenesis therapy, and surgical resection.

This paper discusses the exponential stability of periodic solutions for stochastic neural networks with multiple time-varying delays. For these networks, sufficient conditions in the linear matrix inequality forms are rare in the literature. We constructed an appropriate Lyapunov-Krasovskii functional to eliminate the items with multiple delays and establish some sufficient conditions in linear matrix inequality forms, to ensure exponential stability of the periodic solutions. Several examples are provided to demonstrate that our results are effective and less conservative than previous ones.

Abstract Background This study aimed to investigate the clinicopathological features and prognostic indicators of primary pulmonary adenoid cystic carcinoma (PACC). Methods Clinical data were collected from 64 primary PACC patients and analyzed retrospectively at the Tianjin Medical University General Hospital, the West China Hospital of Sichuan University, the First Affiliated Hospital of Guangxi Medical University, and the Bishan Hospital of Chongqing Medical University from January 2003 to August 2023. The 64 patients (28 males and 36 females) were aged from 20 to 73 years, with a median age of 49 years and an average age of 49.3 years. Results Immunohistochemical staining showed that the tumors expressed CK7, S‐100 protein, CK5/6, CD117, and p63. Seven patients underwent fluorescence in situ hybridization (FISH) testing and three were found to have myeloblastosis (MYB) gene translocation. In total, 53 patients underwent surgery, among whom 31 received only surgery and 22 received both surgery and postoperative chemoradiotherapy. In addition, 10 patients received chemoradiotherapy only, while one patient underwent treatment with traditional Chinese medicine. The overall survival rates in the first, third, and fifth years were 98.4%, 95.3%, and 87.5%, respectively. Conclusion Prognostic analysis revealed that age, tumor size, lymph node metastasis status, margin status, and choice of treatment modality significantly influenced the patients' prognosis.

Introduction: Malignant pleural mesothelioma (MPM) is a rare and universally lethal malignancy with limited treatment options. Immunotherapy with immune checkpoint inhibitors (ICIs) has recently been approved for unresectable MPM, but response to ICIs is heterogeneous, and reliable biomarkers for prospective selection of appropriate subpopulations likely to benefit from ICIs remain elusive. Methods: We performed multiscale integrative analyses of published primary tumor data set from The Cancer Genome Atlas (TCGA) and the French cohort E-MTAB-1719 to unravel the tumor immune microenvironment of MPM deficient in BAP1, one of the most frequently mutated tumor suppressor genes (TSGs) in the disease. The molecular profiling results were validated in independent cohorts of patients with MPM using immunohistochemistry and multiplex immunohistochemistry. Results: We revealed that BAP1 deficiency enriches immune-associated pathways in MPM, leading to increased mRNA signatures of interferon alfa/gamma response, activating dendritic cells, immune checkpoint receptors, and T-cell inflammation. This finding was confirmed in independent patient cohorts, where MPM tumors with low BAP1 levels are associated with an inflammatory tumor immune microenvironment characterized by increased exhausted precursor T-cells and macrophages but decreased myeloid-derived suppressor cells (MDSCs). In addition, BAP1low MPM cells are in close proximity to T cells and therefore can potentially be targeted with ICIs. Finally, we revealed that BAP1-proficient MPM is associated with a hyperactive mitogen-activated protein kinase (MAPK) pathway and may benefit from treatment with MEK inhibitors (MEKis). Conclusion: Our results suggest that BAP1 plays an immunomodulatory role in MPM and that BAP1-deficient MPM may benefit from immunotherapy, which merits further clinical investigation.

Abstract. As one of the most malignant tumors worldwide, lung cancer, fueled by metastasis, has shown rising mortality rates. However, effective clinical strategies aimed at preventing metastasis are lacking owing to its dynamic multi-step, complicated, and progressive nature. Immunotherapy has shown promise in treating cancer metastasis by reversing the immunosuppressive network of the tumor microenvironment. However, drug resistance inevitably develops due to inadequate delivery of immunostimulants and an uncontrolled immune response. Consequently, adverse effects occur, such as autoimmunity, from the non-specific immune activation and non-specific inflammation in off-target organs. Nanocarriers that improve drug solubility, permeability, stability, bioavailability, as well as sustained, controlled, and targeted delivery can effectively overcome drug resistance and enhance the therapeutic effect while reducing adverse effects. In particular, nanomedicine-based immunotherapy can be utilized to target tumor metastasis, presenting a promising therapeutic strategy for lung cancer. Nanotechnology strategies that boost the immunotherapy effect are classified based on the metastatic cascade related to the tumor immune microenvironment; the breaking away of primary tumors, circulating tumor cell dissemination, and premetastatic niche formation cause distant secondary site colonization. In this review, we focus on the opportunities and challenges of integrating immunotherapy with nanoparticle formulation to establish nanotechnology-based immunotherapy by modulating the tumor microenvironment for preclinical and clinical applications in the management of patients with metastatic lung cancer. We also discuss prospects for the emerging field and the clinical translation potential of these techniques.

Whistler mode waves are critical emissions in magnetized plasmas that usually influence the electron dynamics in a planetary magnetosphere. In this paper, we present a unique event in the Martian magnetosphere in which enhanced whistler mode waves (~10−11 V2/m2/Hz) with frequency of 0.1 fce–0.5 fce occurred, based on MAVEN data, exactly corresponding to a significant decrease of suprathermal electron fluxes. The diffusion coefficients are calculated by using the observed electric field wave spectra. The pitch angle diffusion coefficient can approach 10−2 s−1, which is much larger, by ~100 times, than the momentum diffusion coefficient, indicating that pitch angle scattering dominates the whistler–electron resonance process. The current results can successfully explain the dropout of the suprathermal electrons in this event. This study provides direct evidence for whistler-driven electron losses in the Martian magnetosphere.

Abstract Malignant pleural mesothelioma (MPM) is associated with previous asbestos exposure, while more clinical insights into this disease have come from other case studies. Maximal cytoreduction is critical in disease control and might help to improve the prognosis. Here, a 41‐year‐old female presented with a 6‐month history of a mass detected in the chest wall following resection of a right pleural mesothelioma 2 years previously. A fluorodeoxyglucose positron emission tomography/computed tomography scan showed a right chest wall mass with a blurred boundary 8.9 cm × 3.7 cm in size. The patient had received one cycle of bevacizumab, carboplatin, and pemetrexed, and two cycles of nivolumab, ipilimumab, and gemcitabine 5 months before admission. We subsequently resected the tumor, the involved diaphragm, and the fifth and sixth ribs, and titanium mesh and continuous suture were used to close the thoracic cage. The fixed paraffin‐embedded tissues showed epithelioid pleural mesothelioma. The patient received nivolumab and ipilimumab postoperatively, and no recurrence was detected 16 months after surgery. En bloc resection with reconstructive surgery effectively removed the locally advanced malignancy and restored the biological function of the thorax with a favorable prognosis. Neoadjuvant immunotherapy might therefore be conducive to radical resection and perioperative immunotherapy might improve the prognosis.

Abstract PIWI-interacting RNAs (piRNAs) are small noncoding RNAs that regulate gene expression, yet their molecular functions in neurobiology are unclear. While investigating neurodegeneration mechanisms using human α-syn(A53T)Tg and AβTg;α-syn(A53T)Tg pan-neuronal overexpressing strains, we unexpectedly observed dysregulation of piRNAs. RNAi screening revealed that knock down of piRNA biogenesis genes improved thrashing behavior; further, a tofu-1 gene deletion ameliorated phenotypic deficits in α-syn(A53T)Tg and AβTg;α-syn(A53T)Tg transgenic strains. piRNA expression was extensively downregulated and H3K9me3 marks were decreased after tofu-1 deletion in α-syn(A53T)Tg and AβTg;α-syn(A53T)Tg strains. Dysregulated piRNAs targeted protein degradation genes suggesting that a decrease of piRNA expression leads to an increase of degradation ability in C. elegans. Finally, we interrogated piRNA expression in brain samples from PD patients. piRNAs were observed to be widely overexpressed at late motor stage. In this work, our results provide evidence that piRNAs are mediators in pathogenesis of Lewy body diseases and suggest a molecular mechanism for neurodegeneration in these and related disorders.

Abstract Endonuclease G (ENDOG), a nuclear-encoded mitochondrial intermembrane space protein, is well known to be translocated into the nucleus during apoptosis. Recent studies have shown that ENDOG might enter the mitochondrial matrix to regulate mitochondrial genome cleavage and replication. However, little is known about the role of ENDOG in the cytosol. Our previous work showed that cytoplasmic ENDOG competitively binds with 14-3-3γ, which released TSC2 to repress mTORC1 signaling and induce autophagy. Here, we demonstrate that cytoplasmic ENDOG could also release Rictor from 14-3-3γ to activate the mTORC2-AKT-ACLY axis, resulting in acetyl-CoA production. Importantly, we observe that ENDOG could translocate to the ER, bind with Bip, and release IRE1a/PERK to activate the endoplasmic reticulum stress response, promoting lipid synthesis. Taken together, we demonstrate that loss of ENDOG suppresses acetyl-CoA production and lipid synthesis, along with reducing endoplasmic reticulum stress, which eventually alleviates high-fat diet-induced nonalcoholic fatty liver disease in female mice.

Abstract Previous studies have shown that auroral kilometric radiation (AKR) can play an important role in the magnetosphere‐atmosphere coupling and has the right‐handed extraordinary (R‐X), left‐handed ordinary (L‐O) and left‐handed extraordinary (L‐X) modes. However, the L‐X mode has not been directly observed in the lower latitude magnetosphere yet, probably because of its very limited frequency range. Here, using observations of the Arase satellite on 6 September 2018, we present an AKR event with two distinct bands (8–20 and 300–1000 kHz) around the location: L = 8 and latitude = −37°. The low (high) band is identified as the L‐X (R‐X) mode based on the polarization and frequency ranges. Simulations of 3‐D ray tracing show that most of ray paths with 14 (11 and 18) kHz pass (miss) the location of Arase, basically consistent with observations. Our study provides direct evidence that the L‐X mode can propagate from high latitudes downward to lower latitudes.

Key Clinical Message Primary mediastinum immature teratoma with somatic‐type malignant transformation (SM) is extremely rare, and the clinical prognosis is poor. Immature teratoma with SM is difficult to eradicate by chemotherapy due to poor sensitivity; therefore, surgical resection is recommended whenever possible because it may offer better survival.

Lung cancer poses a global threat to human health, while common cancer treatments (chemotherapy and targeted therapies) have limited efficacy. Immunotherapy offers hope of sustained remission for many patients with lung cancer, but a significant proportion of patients fail to respond to treatment owing to immune resistance. There is extensive evidence to suggest the immunosuppressive microenvironment as the cause of this treatment failure. Numerous studies have suggested that the adenosine (ADO) pathway plays an important role in the formation of an immunosuppressive microenvironment and may be a key factor in the development of immune resistance in EGFR-mutant cell lung cancer. Inhibition of this pathway may therefore be a potential target to achieve effective reversal of ADO pathway-mediated immune resistance. Recently, an increasing number of clinical trials have begun to address the broad prospects of using the ADO pathway as an immunotherapeutic strategy. However, few researchers have summarized the theoretical basis and clinical rationale of the ADO pathway and immune checkpoint dual blockade in a systematic and detailed manner, particularly in lung cancer. As such, a timely review of the potential value of the ADO pathway in combination with immunotherapy strategies for lung cancer is warranted. This comprehensive review first describes the role of ADO in the formation of a lung tumor-induced immunosuppressive microenvironment, discusses the key mechanisms of ADO inhibitors in reversing lung immunosuppression, and highlights recent evidence from preclinical and clinical studies of ADO inhibitors combined with immune checkpoint blockers to improve the lung cancer immunosuppressive microenvironment.

Chemotherapy combined with immunotherapy has significantly improved survival in patients with extensive-stage small cell lung cancer (ES-SCLC), and neoadjuvant immunotherapy combined with chemotherapy has emerged as the standard treatment for those with resectable non-small cell lung cancer (NSCLC). However, the potential benefits of surgery following neoadjuvant immunotherapy combined with chemotherapy in locally advanced SCLC remain unclear. Herein, we report a patient diagnosed with stage IIIB SCLC, who was administered five cycles of neoadjuvant serplulimab combined with chemotherapy followed by surgery, and subsequently achieved a pathologic complete response (pCR). Within a follow-up duration of six months, the patient displayed neither recurrence nor metastasis and experienced no treatment-related adverse reactions of any grade. Based on this case, for locally advanced SCLC, neoadjuvant serplulimab combined with chemotherapy followed by surgery may present an effective, safe, and potentially curative treatment strategy. Nonetheless, further prospective studies are needed to verify our findings.

The Niutitang Formation of the lower Cambrian (Є1n) is a target reservoir of shale gas widely developed in China’s Middle-Upper Yangtze region, with the characteristics of being widely distributed, having a big thickness and highly organic carbon abundance. However, the exploration and research degree are relatively low. Based on extensive core sample, experimental test results, drilling, and field outcrop surveying, the shale gas generation capacity, gas content, and gas composition are discussed. The preservation conditions of shale gas are then systematically analyzed from the aspects of tectonic movement, fault development, structural style, and thermal evolution degree. The results show that the organic-rich shale with a thickness ranging from 40 to 150 m developed in the mid-lower part of the Є1n Formation, with the TOC content values ranging from 0.4% to 14.64%. While it has unfavorable characteristics of a high thermal evolution, with Ro values ranging from 1.92% to 5.74%, a low gas content and a high nitrogen content (70% wells). The Є1n shale gas has complex preservation conditions. The Є1n Formation has good roof-to-floor conditions, but after the main gas generating peak of the Є1n shale during the Jurassic–Cretaceous, the most intensive tectonic activity of the Yanshan movement resulted in poor preservation conditions (faults developed and cap rock fractured). The huge faults extended to the surface are formed due to tectonic movement in an extensional environment, and the structural style and development are the main factors affecting the preservation conditions of the Є1n shale gas. Additionally, the high thermal evolution of the Є1n shales also has a certain impact on the preservation conditions. Therefore, the stable area far from large faults (>2.0 km), with weak local tectonic activity and tectonic deformation, is the favorable area for shale gas preservation in the Є1n Formation.

Abstract Taking the HD1 well as the research target, through intensive core sampling, experimental test analysis, comprehensive logging interpretation and other methods, the fracability of shale reservoirs was discussed in this paper. The results show that the Gufeng–Dalong Formation in the HD1 well has a high organic carbon content, and the organic-rich shale developed in the lower part of the Gufeng and Dalong Formations with thicknesses of 30 m and 15 m, respectively. For the low-porosity and ultralow-permeability shale reservoir type, the natural fractures are undeveloped in the lower part of the Dalong Formation, with a lower linear density, while they are well developed in the Xiayao and Longtan Formations and the lower part of the Gufeng Formation, and the interlayer bedding fractures are relatively developed. The Gufeng–Dalong Formation shale also has a high mineral brittleness index (average of 44.5%), high static Young’s modulus (20–70 GPa), low static Poisson’s ratio (0.10–0.31), and high horizontal pressure difference coefficient of two phases (0.17–0.56). It is concluded that the shale reservoir is favorable for fracture development in the lower part of the Dalong Formation, with depths of 1249–1289.5 m, and the lower part of the Xiayao, Longtan and Gufeng Formations, with depths of 1300–1335.3 m. Overall, the fracable shale section with high brittleness and rock strength is beneficial to fracturing. However, the existence of a large number of shale bedding fractures increases the complexity of the fractures, and at the same time, it has a certain negative impact on fracture generation. Double wing fractures are easily formed because of the high two-phase horizontal pressure difference. Therefore, the leakage caused by shale bedding fractures and the influence on the fracture height and extension length should be considered comprehensively in fracturing design.

Lung cancer is the malignant tumor with the highest morbidity and mortality in China. Non-small cell lung cancer (NSCLC) is the main pathological subtype of lung cancer. On April 13, 2023, the National Comprehensive Cancer Network (NCCN) released the third edition of the 2023 NCCN Oncology Clinical Practice Guidelines: Non-small Cell Lung Cancer, which reflects the latest advances in international lung cancer research. This article will interpret the main updated contents of the new edition of the guidelines, and compare it with the third edition of the NCCN guidelines in 2022, so as to provide references about the diagnosis and treatment of NSCLC for clinical medical personnel in China.

Metastasis is the leading cause of cancer-related death. Despite extensive treatment, the prognosis for patients with metastatic cancer remains poor. In addition to conventional surgical resection, radiotherapy, immunotherapy, chemotherapy, and targeted therapy, various nanobiomaterials have attracted attention for their enhanced antitumor performance and low off-target effects. However, nanomedicines exhibit certain limitations in clinical applications, such as rapid clearance from the body, low biological stability, and poor targeting ability. Biomimetic methods utilize the natural biomembrane to mimic or hybridize nanoparticles and circumvent some of these limitations. Considering the involvement of immune cells in the tumor microenvironment of the metastatic cascade, biomimetic methods using immune cell membranes have been proposed with unique tumor-homing ability and high biocompatibility. In this review, we explore the impact of immune cells on various processes of tumor metastasis. Furthermore, we summarize the synthesis and applications of immune cell membrane-based nanocarriers increasing therapeutic efficacy against cancer metastases via immune evasion, prolonged circulation, enhanced tumor accumulation, and immunosuppression of the tumor microenvironment. Moreover, we describe the prospects and existing challenges in clinical translation.

Alzheimer’s and related diseases are significant health issues of this era. The interdisciplinary use of deep learning in this field has shown great promise and gathered considerable interest. This paper surveys deep learning literature related to Alzheimer’s disease, mild cognitive impairment, and related diseases from 2010 to early 2023. We identify the major types of unsupervised, supervised, and semi-supervised methods developed for various tasks in this field, including the most recent developments, such as the application of recurrent neural networks, graph-neural networks, and generative models. We also provide a summary of data sources, data processing, training protocols, and evaluation methods as a guide for future deep learning research into Alzheimer’s disease. Although deep learning has shown promising performance across various studies and tasks, it is limited by interpretation and generalization challenges. The survey also provides a brief insight into these challenges and the possible pathways for future studies.

Maybe because Cohen-Grossberg neural networks with multiple time-varying delays and distributed delays cannot be converted into the vector-matrix forms, the stability results of such networks are relatively few and the stability conditions in the linear matrix inequality forms have not been established. So this paper investigates the exponential stability of the networks and gives the sufficient condition in the linear matrix inequality forms. Two examples are provided to demonstrate the effectiveness of the theoretical results.

Abstract C11orf54 is an ester hydrolase highly conserved across different species. C11orf54 has been identified as a biomarker protein of renal cancers, but its exact function remains poorly understood. Here we demonstrate that C11orf54 knockdown decreases cell proliferation and enhances cisplatin-induced DNA damage and apoptosis. On the one hand, loss of C11orf54 reduces Rad51 expression and nuclear accumulation, which results in suppression of homologous recombination repair. On the other hand, C11orf54 and HIF1A competitively interact with HSC70, knockdown of C11orf54 promotes HSC70 binding to HIF1A to target it for degradation via chaperone-mediated autophagy (CMA). C11orf54 knockdown-mediated HIF1A degradation reduces the transcription of ribonucleotide reductase regulatory subunit M2 (RRM2), which is a rate-limiting RNR enzyme for DNA synthesis and DNA repair by producing dNTPs. Supplement of dNTPs can partially rescue C11orf54 knockdown-mediated DNA damage and cell death. Furthermore, we find that Bafilomycin A1, an inhibitor of both macroautophagy and chaperone-mediated autophagy, shows similar rescue effects as dNTP treatment. In summary, we uncover a role of C11orf54 in regulating DNA damage and repair through CMA-mediated decreasing of HIF1A/RRM2 axis.

Abstract Infertility is a worldwide reproductive health problem and there are still many unknown etiologies of infertility. In recent years, increasing evidence emerged and confirmed that epigenetic regulation played a leading role in reproduction. However, the function of m6A modification in infertility remains unknown. Here we report that METTL3-dependent m6A methylation plays an essential role in female fertility via balancing the estrogen and progesterone signaling. Analysis of GEO datasets reveal a significant downregulation of METTL3 expression in the uterus of infertile women with endometriosis or recurrent implantation failure. Conditional deletion of Mettl3 in female reproductive tract by using a Pgr-Cre driver results in infertility due to compromised uterine endometrium receptivity and decidualization. m6A-seq analysis of the uterus identifies the 3’UTR of several estrogen-responsive genes with METTL3-dependent m6A modification, like Elf3 and Celsr2, whose mRNAs become more stable upon Mettl3 depletion. However, the decreased expression levels of PR and its target genes, including Myc, in the endometrium of Mettl3 cKO mice indicate a deficiency in progesterone responsiveness. In vitro, Myc overexpression could partially compensate for uterine decidualization failure caused by Mettl3 deficiency. Collectively, this study reveals the role of METTL3-dependent m6A modification in female fertility and provides insight into the pathology of infertility and pregnancy management.

Rolling represents an essential stage in congou black tea processing. However, the influence of rolling pressure on tea flavor and non-volatile compounds remains unclear. Herein, a combination of untargeted metabolomics, tea pigments quantification, E-tongue, colorimeter and sensory evaluation was used to evaluate the effect of rolling pressure on black tea quality. As the rolling pressure increased, theaflavins (TFs), thearubigins (TRs), and theabrownins (TBs) significantly elevated. The tea metabolic profiles fluctuated and 47 metabolites were identified as key differential metabolites including flavan-3-ols, flavonol/flavone glycosides, phenolic acids, amino acids. These substances altered possibly due to the variations in enzymatic oxidation of tea phenolics and amino acids. Overall, black tea with moderate rolling pressure presented higher sweetness, lower bitterness, and higher quality index (10 TFs + TRs)/TBs. The results were verified by a validation batch. This study provided new insights into the regulation of rolling pressure and a guidance for black tea processing.

Cell counting and segmentation are critical tasks in biology and medicine. The traditional methods for cell counting are labor‐intensive, time‐consuming, and prone to human errors. Recently, deep learning‐based cell counting methods have become a trend, including point‐based counting methods, such as cell detection and cell density prediction, and non‐point‐based counting, such as cell number regression prediction. However, the point‐based counting method heavily relies on well‐annotated datasets, which are scarce and difficult to obtain. On the other hand, nonpoint‐based counting is less interpretable. The task of cell counting by dividing it into two subtasks is approached: cell number prediction and cell distribution prediction. To accomplish this, a deep learning network for spatial‐based super‐resolution reconstruction (SSRNet) is proposed that predicts the cell count and segments the cell distribution contour. To effectively train the model, an optimized multitask loss function (OM loss) is proposed that coordinates the training of multiple tasks. In SSRNet, a spatial‐based super‐resolution fast upsampling module (SSR‐upsampling) is proposed for feature map enhancement and one‐step upsampling, which can enlarge the deep feature map by 32 times without blurring and achieves fine‐grained detail and fast processing. SSRNet uses an optimized encoder network. Compared with the classic U‐Net, SSRNet's running memory read and write consumption is only 1/10 of that of U‐Net, and the total number of multiply and add calculations is 1/20 of that of U‐Net. Compared with the traditional sampling method, SSR‐upsampling can complete the upsampling of the entire decoder stage at one time, reducing the complexity of the network and achieving better performance. Experiments demonstrate that the method achieves state‐of‐the‐art performance in cell counting and segmentation tasks. The method achieves nonpoint‐based counting, eliminating the need for exact position annotation of each cell in the image during training. As a result, it has demonstrated excellent performance on cell counting and segmentation tasks. The code is public on GitHub (https://github.com/Roin626/SSRnet).

Abstract Stage III non‐small cell lung cancer (NSCLC) encompasses a group of diseases with high heterogeneity. Such patients should actively receive comprehensive treatments. It is imperative for all stage III NSCLC patients to receive consultation with a multiple disciplinary team, which allows the development of a proposal for clinical diagnosis and treatment. In this consensus, stage III NSCLC is divided into two types (operable and inoperable) according to different clinical conditions. Resectable NSCLC is further subdivided into two conditions (with or without driver genes). For each clinical scenario, this consensus emphasizes that the foundation of any medical decisions regarding the optimal diagnostic or therapy procedure is scientific evidence from clinical research. Finally, based on the level of evidence and strength of recommendations, this consensus provides recommendations for the management of stage III NSCLC from six perspectives. The objective of this consensus is to help clinicians choose the best treatment and promote the standardization of stage III NSCLC diagnosis and treatment in China.

Global exponential periodicity of nonlinear neural networks with multiple time-varying delays is investigated. Such neural networks cannot be written in the vector-matrix form because of the existence of the multiple delays. It is noted that although the neural network with multiple time-varying delays has been investigated by Lyapunov-Krasovskii functional method in the literature, the sufficient conditions in the linear matrix inequality form have not been obtained. Two sets of sufficient conditions in the linear matrix inequality form are established by Lyapunov-Krasovskii functional and linear matrix inequality to ensure that two arbitrary solutions of the neural network with multiple delays attract each other exponentially. This is a key prerequisite to prove the existence, uniqueness, and global exponential stability of periodic solutions. Some examples are provided to demonstrate the effectiveness of the established results. We compare the established theoretical results with the previous results and show that the previous results are not applicable to the systems in these examples.

Abstract Background Lung cancer screening may provide a “teachable moment” for the smoking cessation and relapse prevention. However, the impact of lung cancer screening on smoking initiation in non‐smokers has not been reported. Methods A baseline smoking behavior survey was conducted in 2000 participants who were screened by low‐dose computed tomography (LDCT) from 2014 to 2018. All participants were re‐surveyed on their smoking behavior in 2019. Of these, 312 participants were excluded, leaving 1688 participants in the final analysis. The smoking initiation rate in baseline non‐smokers, the relapse rate in baseline former smokers, and the abstinence rate in baseline current smokers were calculated, respectively. The associations between screening results, demographic characteristics, and smoking behavior change were analyzed using multivariable logistic regression. Results From 2014 to 2019, smoking prevalence significantly decreased from 52.6% to 49.1%. The prevalence of smoking initiation, relapse, and abstinence in baseline non‐smokers, former, and current smokers was 16.8%, 22.9%, and 23.7%, respectively. The risk of smoking initiation in baseline non‐smokers was significantly higher in those with negative screening result (adjusted OR = 2.97, 95% CI: 1.27–6.94). Compared to smokers who only received baseline screening, the chance of smoking abstinence in baseline current smokers was reduced by over 80% in those who attended 5 rounds of screening (adjusted OR = 0.15, 95% CI:0.08–0.27). No significant associations were found between smoking relapse and prior screening frequency, with at least one positive screening result. Age, gender, occupational exposure, income, and smoking pack years were also associated with smoking behavior changes. Conclusions The overall decreased smoking prevalence indicated an overwhelming effect of “teachable moment” on “license to smoke.” A tailored smoking cessation strategy should be integrated into lung cancer screening.

Abstract Background To investigate the correlation between the preoperative systemic immune‐inflammation index (pSII) and postoperative pneumonia (POP) in surgical non‐small cell lung cancer patients. Methods Patients who underwent lung cancer surgery at West China Hospital of Sichuan University were retrospectively included. The indicators were collected, including basic information of patients, surgery‐related variables and POP rate. The predictive value of the pSII in the occurrence of POP was analyzed. Results A total of 1486 patients (male: 748, 50.3%; female: 738, 49.7%; mean age: 58.2 ± 9.7 years; median age: 59 years old, interquartile range: 51–65 years old) were finally included in the study, of which 142 patients had POP with an incidence of 9.5% (142/1486), 9.2% (69/748) in males, and 9.9% (73/738) in females. The proportion of patients with diabetes in the pneumonia group was significantly higher than that in the nonpneumonia group (9.8%, 14/142 vs. 5.6%, 75/1344, p = 0.041). Compared with the nonpneumonia group, the level of the preoperative body mass index (24.2 [21.9, 26.1] vs. 23.1 [21.1, 25.2], p = 0.003) and SII (487 [350, 673] vs. 345 [230, 500], p

Abstract A meta‐analysis on seven large case series (>1000 cases) of chromosome microarray analysis (CMA) on products of conceptions (POC) evaluated the diagnostic yields of genomic disorders and syndromic pathogenic copy number variants (pCNVs) from a collection of 35,130 POC cases. CMA detected chromosomal abnormalities and pCNVs in approximately 50% and 2.5% of cases, respectively. The genomic disorders and syndromic pCNVs accounted for 31% of the detected pCNVs, and their incidences in POC ranged from 1/750 to 1/12,000. The newborn incidences of these genomic disorders and syndromic pCNVs were estimated in a range of 1/4000 to 1/50,000 live births from population genetic studies and diagnostic yields of a large case series of 32,587 pediatric patients. The risk of spontaneous abortion (SAB) for DiGeorge syndrome (DGS), Wolf–Hirschhorn syndrome (WHS), and William–Beuren syndrome (WBS) was 42%, 33%, and 21%, respectively. The estimated overall risk of SAB for major genomic disorders and syndromic pCNVs was approximately 38%, which was significantly lower than the 94% overall risk of SAB for chromosomal abnormalities. Further classification on levels of risk of SAB to high (>75%), intermediate (51%–75%), and low (26%–50%) for known chromosomal abnormalities, genomic disorders, and syndromic pCNVs could provide evidence‐based interpretation in prenatal diagnosis and genetic counseling.

IntroductionLycium barbarum glycopeptide (LbGp) is the main bioactive compound extracted from the traditional Chinese medicine. L. barbarum berries and has been proven to have numerous health benefits, including antioxidative, anti-inflammatory, anticancer, and cytoprotective activities. However, the antiaging effect of LbGp remains unknown.MethodsThe lifespan and body movement of C. elegans were used to evaluate the effect of LbGp on lifespan and health span. The thrashing assay was used to determine the role of LbGp in Parkinson’s disease. To investigate the mechanisms of LbGp-induced antiaging effects, we analyzed changes in lifespan, movement, and the expression of longevity-related genes in a series of worm mutants after LbGp treatment.ResultsWe found that LbGp treatment prolonged the lifespan and health span of C. elegans. Mechanistically, we found that LbGp could activate the transcription factors DAF-16/FOXO, SKN-1/Nrf2, and HSF-1, as well as the nuclear receptor DAF-12, thereby upregulating longevity-related genes to achieve lifespan extension. In addition, we found that the lifespan extension induced by LbGp partially depends on mitochondrial function. Intriguingly, LbGp also ameliorated neurodegenerative diseases such as Parkinson’s disease in a DAF-16-, SKN-1-, and HSF-1-dependent manner.ConclusionOur work suggests that LbGp might be a viable candidate for the treatment and prevention of aging and age-related diseases.

Background and objective Acquired and primary resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is still the bottleneck of clinical treatment of advanced non-small cell lung cancer (NSCLC). STE029 is a novel anticancer drug which consists of 3-hydroxy-3-methylglutarylcoenzyme A reductase (HMGCR) inhibitor and novel cancer cell membrane targeting molecular. This study aimed to investigate the reversal mechanism of EGFR-TKI resistance by STE029 in lung adenocarcinoma. Methods CCK8 test was used to test the cell viability and survival rate of EGFR mutated PC9 cell (Gefitinib sensitive), PC9/BB4 cell (acquired Gefitinib resistant), and EGFR wild type A549 cell after treatment of STE029, Gefitinib or combination of both. EdU test was applied to detect changes in cell cycle and Hoechst 33258 was applied to detect apoptosis rate in overcoming the EGFR-TKI resistance. The activity of EGFR/PI3K/Akt, cell cycle and apoptosis signal pathways were examined. In vivo, nude mice were exposed to STE029, Gefitinib and STE029+Gefitinib for 5 wk. And the the tumor volume was measured and tumor weight was obtained on the last day. Results (1) PC9 cells was highly sensitive to Gefitinib, while PC9/BB4 and A549 cell showed significant resistance to Gefitinib treatment; (2) STE029+Gefitinib treatment could significantly decrease the 50% inhibitory concentrarion (IC50) of Gefitinib in PC9, PC9/BB4 and A549 cells (P0.05); However, apoptosis rate was increased in STE029+Gefitinib group in A549 cell (P0.05). (4) In PC9 and PC9/BB4 cells, the combination of STE029 and Gefitinib could downregulate p-EGFR, p-Akt, p-Cyclin D1 and Cyclin D1 (P0.05). In A549 cells, the combination of STE029 and Gefitinib could downregulate p-Akt (P

Abstract This meta‐analysis aimed to evaluate the feasibility and oncological outcomes between video‐assisted thoracic surgery (VATS) and thoracotomy for non–small cell lung cancer (NSCLC) patients with pathologic N2 (pN2) disease. Data for analysis included short‐term outcomes and long‐term outcomes. We calculated the weighted mean differences (WMDs) for continuous data and the results of overall survival (OS) and disease free survival (DFS) were pooled using the hazard ratios (HRs) with 95% confidence intervals (CIs). Heterogeneity was assessed using the Q‐test and I2‐test. Sensitivity analysis was performed to further examine the stability of pooled HRs and WMDs. In the pooled analyses of 10 eligible studies, results showed that VATS for NSCLC patients with pN2 disease yielded significantly less blood loss (WMD = −61.43; 95% confidence intervals [CI], [−87.69, −35.18]; p

Abstract The mouse vaginal epithelium cyclically exhibits cell proliferation and differentiation in response to estrogen. Estrogen acts as an activator of mTOR signaling but its role in vaginal epithelial homeostasis is unknown. We analyzed reproductive tract-specific Rptor or Rictor conditional knockout mice to reveal the role of mTOR signaling in estrogen-dependent vaginal epithelial cell proliferation and differentiation. Loss of Rptor but not Rictor in the vagina resulted in an aberrant proliferation of epithelial cells and failure of keratinized differentiation. As gene expression analysis indicated, several estrogen-mediated genes, including Pgr and Ereg (EGF-like growth factor) were not induced by estrogen in Rptor cKO mouse vagina. Moreover, supplementation of EREG could activate the proliferation and survival of vaginal epithelial cells through YAP1 in the absence of Rptor. Thus, mTORC1 signaling integrates estrogen and growth factor signaling to mediate vaginal epithelial cell proliferation and differentiation, providing new insights into vaginal atrophy treatment for post-menopausal women.

Abstract Background Primary pulmonary osteosarcoma (PPOS) is an uncommon malignancy originating from the lung with low incidence, and its clinical characteristics and prognosis have not been systematically reported. Therefore, we aimed to recognize the prognostic factors and constructed a survival prediction model for PPOS. Methods We collected the data from the Surveillance, Epidemiology, and End Results database and systematic review of previous studies. Demographical and clinical characteristics, radiographic manifestations, treatment modalities, and prognosis were analyzed. A prediction model via nomogram was constructed and then evaluated by the concordance index (C-index) and the receiver operating characteristic (ROC) curve. Results A total of 49 cases were included for analysis with a median age of 67 years old (range 33–94 years), of which 32 (65.3%) were male. The median size was 6 cm (range 1.8-25 cm), and the median overall survival (OS) was eight months (interquartile range 4.5–12 months) with a 1-year OS rate of 30.8%. Tumor size over 7 cm (hazard ratio [HR] = 2.98; P = 0.018) and those without microscopic findings of osteoid found in the tumors (HR = 2.11; P = 0.048) were referred to a poor OS, while surgery was associated with an improved OS (HR = 0.20; P

Abstract Purpose To study the prognostic value of the prognostic nutritional index (PNI) in advanced cancers receiving programmed death‐1/programmed death‐ligand 1 (PD‐1/L1) inhibitors. Methods Online electronic databases were comprehensively searched and available literature was retrieved. We extracted available data from included researches and pooled the hazard ratios (HRs) and 95% confidence intervals (CIs) to learn the prognostic value of PNI on overall survival (OS) or progression‐free survival (PFS); and meanwhile calculated the relative risk (RR) with 95% CI to study the relationship between PNI and treatment efficacy (objective response rate [ORR] or disease control rate [DCR]) in late staged cancer receiving PD‐1/L1 inhibitors. Results Nine studies were finally selected for this meta‐analysis. We obtained data regarding PNI on OS from all nine studies, and the pooled HR was 2.31 (95% CI 1.81–2.94, p = 0.000), showing a correlation between low PNI and worse OS. Eight studies reported a relationship between PNI and PFS, and combined results revealed shorter PFS in patients with lower PNI, with an HR of 1.75 (95% CI 1.40–2.18, p = 0.000). Four studies explored the association between PNI and ORR and two studies explored the influence of PNI on DCR. An association between PNI and ORR (RR = 0.47, p = 0.003) was observed, while no association between PNI and DCR (RR = 0.49, p = 0.103) was observed by pooling these studies. Conclusion In summary, this meta‐analysis indicated that a lower PNI was significantly correlated with decreased OS and PFS and played adverse roles in ORR in advanced cancer patients receiving PD‐1/L1 inhibitors. Therefore, PNI could be promising for predicting prognosis and treatment response in advanced malignancies treated with PD‐1/L1 inhibitors.

Abstract Electron cyclotron harmonic (ECH) waves, which are responsible for the diffuse aurora, are usually observed with the strongest intensity in the first band. Here, we present observations of enhanced higher‐band ECH with wave intensities above 10−3 mV2m−2 Hz−1 by Van Allen Probes. Fully thermal simulation results indicate that these waves can be locally excited by the observed electron distributions, and higher plasma density and lower magnetic strength are favorable for generating the enhanced higher‐band ECH. The pitch angle diffusion coefficient Dαα of the higher‐band ECH can exceed 10−5 s−1 inside the loss cone for energetic electrons (300 eV–∼15 keV), greater than the momentum diffusion coefficient Dpp by ∼100 times. It is suggested that the enhanced higher‐band ECH can also efficiently scatter these electrons into the loss cone and contribute to the diffuse aurora.

Cancer is a disease with ecological and evolutionary unity, which seriously affects the survival and quality of human beings. Currently, many reports have suggested Gas6 plays an important role in cancer. Binding of gas6 to TAM receptors is associated with the carcinogenetic mechanisms of multiple malignancies, such as in breast cancer, chronic lymphocytic leukemia, non-small cell lung cancer, melanoma, prostate cancer, etc., and shortened overall survival. It is accepted that the Gas6/TAM pathway can promote the malignant transformation of various types of cancer cells. Gas6 has the highest affinity for Axl, an important member of the TAM receptor family. Knockdown of the TAM receptors Axl significantly affects cell cycle progression in tumor cells. Interestingly, Gas6 also has an essential function in the tumor microenvironment. The Gas6/AXL pathway regulates angiogenesis, immune-related molecular markers and the secretion of certain cytokines in the tumor microenvironment, and also modulates the functions of a variety of immune cells. In addition, evidence suggests that the Gas6/AXL pathway is involved in tumor therapy resistance. Recently, multiple studies have begun to explore in depth the importance of the Gas6/AXL pathway as a potential tumor therapeutic target as well as its broad promise in immunotherapy; therefore, a timely review of the characteristics of the Gas6/AXL pathway and its value in tumor treatment strategies is warranted. This comprehensive review assessed the roles of Gas6 and AXL receptors and their associated pathways in carcinogenesis and cancer progression, summarized the impact of Gas6/AXL on the tumor microenvironment, and highlighted the recent research progress on the relationship between Gas6/AXL and cancer drug resistance.

BackgroundUnderstanding the effects of demographic drivers on lung cancer mortality trends is critical for lung cancer control. We have examined the drivers of lung cancer mortality at the global, regional, and national levels.MethodsData on lung cancer death and mortality were extracted from the Global Burden of Disease (GBD) 2019. Estimated annual percentage change (EAPC) in the age-standardized mortality rate (ASMR) for lung cancer and all-cause mortality were calculated to measure temporal trends in lung cancer from 1990 to 2019. Decomposition analysis was used to analyze the contributions of epidemiological and demographic drivers to lung cancer mortality.ResultsDespite a non-significant decrease in ASMR [EAPC = −0.31, 95% confidence interval (CI): −1.1 to 0.49], the number of deaths from lung cancer increased by 91.8% [95% uncertainty interval (UI): 74.5–109.0%] between 1990 and 2019. This increase was due to the changes in the number of deaths attributable to population aging (59.6%), population growth (56.7%), and non-GBD risks (3.49%) compared with 1990 data. Conversely, the number of lung cancer deaths due to GBD risks decreased by 19.8%, mainly due to tobacco (−12.66%), occupational risks (−3.52%), and air pollution (−3.47%). More lung cancer deaths (1.83%) were observed in most regions, which were due to high fasting plasma glucose levels. The temporal trend of lung cancer ASMR and the patterns of demographic drivers varied by region and gender. Significant associations were observed between the contributions of population growth, GBD risks and non-GBD risks (negative), population aging (positive), and ASMR in 1990, the sociodemographic index (SDI), and the human development index (HDI) in 2019.ConclusionPopulation aging and population growth increased global lung cancer deaths from 1990 to 2019, despite a decrease in age-specific lung cancer death rates due to GBD risks in most regions. A tailored strategy is needed to reduce the increasing burden of lung cancer due to outpacing demographic drivers of epidemiological change globally and in most regions, taking into account region- or gender-specific risk patterns.

Abstract Magnetosonic (MS) wave is one of the most common electromagnetic emissions in the magnetosphere, while quasi‐electrostatic magnetosonic (QEMS) waves are seldom observed. Here we present an interesting QEMS event detected by Van Allen Probe A on 9 January 2014, in which the presence of multi‐band QEMS emissions shows evident correlations with relatively low plasma densities (∼10 cm−3) and enhancements of suprathermal (∼10 − 100 eV) proton fluxes. Based on the observed proton distributions, simulations demonstrate very similar profiles to the observed QEMS in the wave spectral characteristics. Parametric studies indicate that the QEMS growth rate can increase by ∼20 times with the plasma density decreasing from 50 to 10 cm−3. Effective growth rates of higher‐band QEMS occur when the suprathermal proton population is sufficiently large. This study reveals that low densities and large suprathermal proton populations are favorable for generating distinct multi‐band QEMS in the magnetosphere.

The magneto-electro-elastic (MEE) medium is a typical intelligent material with promising application prospects in sensors and transducers, whose thermal contact response is responsible for their sensitivity and stability. An effective thermal contact model between a moving sphere and a coated MEE medium with transverse isotropy is established via a semi-analytical method (SAM) to explore its thermal contact response. First, a group of frequency response functions for the magneto-electro-thermo-elastic field of a coated medium are derived, assuming that the coating is perfectly bonded to the substrate. Then, with the aid of the discrete convolution–fast Fourier transform algorithm and conjugate gradient method, the contact pressure and heat flux can be determined. Subsequently, the induced elastic, thermal, electric and magnetic fields in the coating and substrate can be obtained via influence coefficients relating the induced field and external loads. With the proposed method, parametric studies on the influence of the sliding velocity and coating property are conducted to investigate the thermal contact behavior and resulting field responses of the MEE material. The sliding velocity and thermal properties of the coating have a significant effect on the thermal contact response of the MEE material; the coupled multi-field response can be controlled by changing the coating thickness between ~0.1 a0 and a0.