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Abstract Nutrient competition with indigenous microbes or pathogens presents a significant challenge for oral probiotic efficacy. To address this issue, we develop an ameba-inspired food-carrying strategy (AIFS) by prebinding ginger-derived exosome-like nanoparticles (GELNs) onto probiotics as food depots. AIFS enables probiotics to efficiently and exclusively consume GELNs in situ, even in the presence of competing bacteria. This results in up to 21 times higher uptake efficiency compared to unengineered probiotics, dramatically accelerating probiotic proliferation. Meanwhile, AIFS potentiates probiotics’ resistance to multiple GI stressors. In a murine model of colitis, AIFS can improve the abundance of probiotics and inhibit pathogens, maintaining intestinal flora homeostasis. Additionally, it can upregulate the anti-inflammatory IL-10, reduce the proinflammatory IL-1β, and repair damaged intestinal mucus. Thereby, AIFS displays potently elevated prophylactic and therapeutic efficacy for colitis mice. This work provides a method for microbial engineering, with broad implications for microbiotherapy and gut health.

Abstract Immune checkpoint inhibitors (ICIs) have changed the treatment landscape for patients with non-small cell lung cancer (NSCLC). In spite of durable responses in some patients, many patients develop early disease progression during the ICI treatment. Thus, early identification of patients with no durable benefit would facilitate the clinical decision for these patients. In this prospective, multicenter study, 101 non-EGFR/ALK patients who received ICI treatment were enrolled after screening 328 stage III-IV NSCLC patients. At the date of cutoff, 83 patients were eligible for ICI efficacy evaluation, with 56 patients having progress-free survival (PFS) over 6 months, which was defined as durable clinical benefit (DCB). A multimodal model was established by integrating normalized bTMB, early dynamic of ctDNA and the first RECIST response. This model could robustly predict DCB with area under the curve (AUC) of 0.878, sensitivity of 79.2% at 86.4% specificity (accuracy = 80.0%). This model was further validated in the independent cohort of the DIREct-On study with AUC of 0.887, sensitivity of 94.7% at 85.3% specificity (accuracy = 90.3%). Patients with higher predict scores had substantially longer PFS than those with lower scores (training cohort: median PFS 13.6 vs 4.2 months, P

Abstract ERBB2 (HER2) represents a newly recognized actionable oncogenic driver in non-small cell lung cancer (NSCLC), with approved targeted therapy available. Understanding the landscape of ERBB2 alterations and co-occurring mutations is essential for guiding treatment decisions. We conducted an analysis involving 3000 NSCLC patients with all types of ERBB2 alterations, drawn from two extensive retrospective cohorts: 1281 from Geneplus (Chinese) and 1719 from Guardant360 (the United States, US). The incidence of all types of ERBB2 alterations was found to be 5.6% in the Chinese group and 5.2% in the US group. In both cohorts, among oncogenic alterations of ERBB2, exon 20 insertion Y772_A775dupYVMA was the most frequent alteration (58% vs 41.6% in the Chinese vs the US), followed by G776delinsVC/LC/VV/IC (10.7% vs 9.7%), and S310X (10.5% vs 15.4%). EGFR ex20 insertions were identified in the A767-V774 region, whereas ERBB2 ex20 insertions were observed in the Y772-P780 region. Notably, EGFR ex20 insertions exhibited greater insertion diversity. Clinical characteristics of EGFR and ERBB2 ex20 NSCLC were similar, characterized by low tumor mutation burden (TMB), a predominant never-smoker population, and a majority of lung adenocarcinoma cases.

Abstract Background Aquatic activities are becoming increasingly popular as a form of exercise during pregnancy. However, the effects of these activities on the physical and mental health outcomes of pregnant women during and after pregnancy as well as fetal outcomes remain unclear. This meta-analysis evaluated the current evidence regarding the effects of aquatic activities during pregnancy on neonatal and maternal outcomes. Methods Three databases (PubMed, Cochrane Central electronic database, Embase) were searched from inception to July 17, 2024 for randomized controlled trials (RCTs) comparing the effects of aquatic activities versus standard prenatal care or no exercise on neonatal and maternal outcomes. Pooled outcome measures were determined using random-effects models. Results Ten RCTs including 1949 patients met the criteria for inclusion in this meta-analysis. The results showed that prenatal aquatic activities could significantly improve maternal weight control (mean difference [MD]= -0.91, 95% confidence interval [CI]= -1.64 to -0.18, P = 0.01, I2 = 0.00%), improve maternal quality of life (standard mean difference [SMD] = 0.16, 95%CI = 0.03 to 0.28, P = 0.01, I2 = 0.00%), and extend fetal birth length (MD = 0.48, 95%CI = 0.10 to 0.87, P = 0.01, I2 = 0.00%) compared with standard prenatal care or no exercise, while no significant differences were observed in fetal birth weight, Apgar score at 1 min, Apgar score at 5 min, pH of umbilical cord blood, gestational age, rate of preterm delivery, incidence of postnatal depression and mode of delivery. Conclusions Prenatal aquatic activities can significantly improve maternal weight control and quality of life during pregnancy, and may promote longer birth length. However, additional studies are needed to confirm these findings.

Background: Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory condition often triggered by malignancies, especially T/NK-cell lymphoma-associated HLH (T/NK-LAHLH). Epstein-Barr virus (EBV) infection is strongly linked to T/NK-LAHLH and worsens prognosis. However, the prognostic value of whole-blood EBV DNA levels in T/NK-LAHLH remains unclear, necessitating further investigation to improve risk assessment and treatment strategies. Objective: To investigate the clinical characteristics and prognostic significance of whole-blood EBV DNA status in patients with T/NK-LAHLH. Design: A single-center, retrospective study was conducted, including 85 patients diagnosed with T/NK-LAHLH between January 2017 and August 2022. Patients were categorized based on EBV DNA status, and clinical outcomes were compared. Methods: EBV DNA levels were quantified using polymerase chain reaction (PCR) assays. Kaplan-Meier survival and Cox regression models to assess overall survival (OS) and identify independent prognostic factors. Results: A total of 85 T/NK-LAHLH patients were included, with a median age of 52 years (range: 18–81 years) and 60% male. The OS rates at 1, 3, 6, and 12 months were 66.6%, 49.8%, 33.8%, and 28.4%, respectively. Among these patients, 67 (78.8%) were EBV DNA-positive, while 18 (21.2%) were EBV DNA negative. EBV DNA-positive patients exhibited significantly lower platelet and globulin levels, higher IL-10 levels, and prolonged activated partial thromboplastin time compared to EBV DNA-negative patients ( p < 0.05). The 6-month OS rate was significantly lower in EBV DNA-positive patients compared to EBV DNA-negative patients (22.5% vs 75.1%, p < 0.001). Multivariate analysis identified EBV DNA positivity as an independent risk factor for shorter 6-month OS (hazard ratio (HR): 4.715; 95% CI: 1.662–13.377; p = 0.004). Among the four patients who underwent allogeneic hematopoietic stem cell transplantation, all achieved complete remission and remained alive at the last follow-up. Conclusion: Whole-blood EBV DNA positivity is a significant prognostic factor for poor outcomes in T/NK-LAHLH patients. These findings highlight the need for incorporating EBV DNA monitoring into clinical management and further research to refine therapeutic strategies.

BackgroundAnaplastic lymphoma kinase (ALK) rearrangement, the most common oncogenic rearrangement in lung adenocarcinoma, occurs in approximately 5% of non-small cell lung cancer (NSCLC) patients. EML4 gene is the most common partner of ALK rearrangement, and distinct EML4-ALK fusions differ in their responsiveness to ALK tyrosine kinase inhibitors. However, the concurrence of two ALK rearrangements in one patient and whose response to ALK-TKIs have rarely been reported so far.Case presentationA 47-year-old Chinese male was diagnosed with stage IV lung adenocarcinoma with multiple intracranial metastases and adrenal metastasis. After progression of two lines of chemotherapy combined with local radiotherapy regimens, his tumor tissue sample was sent to perform the DNA-based next-generation sequencing of 116 genes. Surprisingly, EML4-ALK (E13:A20) fusion and a novel SV2B-ALK (S6:A20) fusion were concurrently identified, which was confirmed using immunohistochemistry and fluorescence in-situ hybridization. Given the superior efficacy of alectinib, the patient received alectinib in the third-line setting with the progression-free survival over 14 months up to now. Moreover, through comprehensive review of previous literatures, a total of 22 patients with multiple ALK fusions and their response to ALK-TKIs were summarized.ConclusionThis is the first report of a NSCLC patient with a novel SV2B-ALK, EML4-ALK double-fusion benefiting from alectinib. Alectinib may be an effective therapeutic option for both primary and metastatic lesions including brain metastases in the late-line setting in NSCLC patients with double-ALK fusion.

Epidemiological studies show a positive association between air pollution and age-related cataracts, but the pathogenic mechanism remains unclear. This study first demonstrates that fine particulate matter (PM2.5) induces ferroptosis in the lens, leading to morphological and functional disorders, through human, animal, and cellular samples. In 3-week PM2.5-exposed rat models (10 µl 1 mg/ml PM2.5 suspension per eye, 4 times a day), we find that many vacuoles form in the lens equatorial region by analysis of haematoxylin and eosin staining after PM2.5 exposure. Using iron and glutathione (GSH) assay kits, we found increased Fe2+ contents and decreased GSH levels in PM2.5-exposed rats’ lenses. Additionally, the lipid peroxide 4-hydroxynonenal (4-HNE) was also found to be elevated with immunoblot, suggesting ferroptosis is involved. Ferroptosis was also observed in human lens epithelial cells treated with 25, 50, and 100 µg/ml PM2.5 suspension for 24 h, accompanied by decreased cell viability and migration. Furthermore, we collect about 60 human lens anterior capsule (HLAC) samples for RNA-seq. The results show that compared to HLACs from areas with PM2.5 concentration ≤30 μg/m³, ferroptosis-related genes expression of those from areas with PM2.5 concentration ≥35 μg/m³ are significantly altered, such as glutathione peroxidase 4 and STEAP family member 3. Also, human lens in areas with high PM2.5 concentrations showed elevated levels of transferrin receptor and 4-HNE with immunoblot, and down-regulated expression of connexin 43 (Cx43) through immunofluorescent. These results demonstrate that ferroptosis plays a key role in PM2.5-induced cataractogenesis.

The prospect of employing chemoimmunotherapy targeted towards the endoplasmic reticulum (ER) presents an opportunity to amplify the synergistic effects of chemotherapy and immunotherapy. In this study, we initially validated celastrol (CEL) as an inducer of immunogenic cell death (ICD) by promoting ER stress and autophagy in colorectal cancer (CRC) cells. Subsequently, an ER-targeted strategy was posited, involving the codelivery of CEL with PD-L1 small interfering RNAs (siRNA) using KDEL peptide-modified exosomes derived from milk (KME), to enhance chemoimmunotherapy outcomes. Our findings demonstrate the efficient transportation of KME to the ER via the Golgi-to-ER pathway. Compared to their non-targeting counterparts, KME exhibited a significant augmentation of the CEL-induced ICD effect. Additionally, it facilitated the release of danger signaling molecules (DAMPs), thereby stimulating the antigen-presenting function of dendritic cells and promoting the infiltration of T cells into the tumor. Concurrently, the ER-targeted delivery of PD-L1 siRNA resulted in the downregulation of both intracellular and membrane PD-L1 protein expression, consequently fostering the proliferation and activity of CD8+ T cells. Ultimately, the ER-targeted formulation exhibited enhanced anti-tumor efficacy and provoked anti-tumor immune responses against orthotopic colorectal tumors in vivo. Collectively, a robust ER-targeted delivery strategy provides an encouraging approach for achieving potent cancer chemoimmunotherapy.

Objective(s): This study aimed to explore the therapeutic effect of fecal microbiota transplantation (FMT) on liver cirrhosis-induced rat models by studying changes in intestinal flora distribution and liver pathology. Materials and Methods: Cirrhosis was induced in adult male Sprague-Dawley rats using carbon tetrachloride; successful establishment of the cirrhosis model was verified using hematoxylin and eosin (HE) staining. Rats were divided into normal control, cirrhosis model+normal saline, and cirrhosis model+FMT groups. Fecal intestinal flora was analyzed using 16S rRNA high-throughput sequencing for each group. Alpha diversity, beta diversity, and functional prediction analyses were performed. Additionally, rat liver tissue was subjected to HE staining to compare the degree of fibrosis and liver damage between the groups.Results: FMT significantly improved the diversity, richness, and uniformity of the intestinal flora in rats with liver cirrhosis. Notably, post-FMT, the abundance of lactobacillaceae, bacilli, and bacteroidia increased, while the abundance of clostridia decreased. Moreover, hepatic fibrosis improved after FMT.Conclusion: The dysbiosis of intestinal flora in rats with liver cirrhosis improved after FMT. Thus, FMT can regulate intestinal flora, reduce liver inflammation, and improve hepatic fibrosis and cirrhosis.

Abstract Background Malignant mesothelioma (MM) is an exceedingly rare tumor with poor prognosis due to the limited availability of effective treatment. Immunotherapy has emerged as a novel treatment approach for MM, but less than 40% of the patients benefit from it. Thus, it is necessary to identify accurate and effective biomarkers that can predict the overall survival (OS) and immunotherapy efficacy for MM. Methods DNA sequencing was used to identify the genomic landscape based on the data from 86 Chinese patients. T cell receptor (TCR) sequencing was used to characterize MM TCR repertoires of 28 patients between October 2016 and April 2023. Results Patients with TP53, NF2, or CDKN2A variants at the genomic level, as well as those exhibiting lower Shannon index (

China’s long-standing dual-track institutions, which differentiate between urban and rural areas, have prioritized urban development, exacerbating the urban–rural divide and contributing to the ongoing decline of rural regions. In response, the “Comprehensive Land Consolidation”(CLC) policy has garnered significant attention from both academics and policymakers. However, there is an urgent need to assess the effectiveness of CLC in revitalizing rural areas. This study aims to quantitatively evaluate the impact of CLC on the reconstruction of rural spaces, including production, living, and ecological spaces (PLES). We examined CLC’s role in shaping rural spaces by developing an evaluation index system and employing the TOPSIS method along with obstacle degree models to measure its effects. Our findings reveal that CLC’s impact on rural spatial reconstruction in Chongqing is D3 (good) and varies across regions. The reconstruction of production and living spaces is more pronounced in metropolitan areas compared to rural-dominated regions in the northeast and southeast. Conversely, the effect on ecological spaces is slightly greater in remote areas than in metropolitan areas. The primary obstacle to effective reconstruction is the vitality of production spaces, though the factors influencing reconstruction differ across regions. Therefore, different regions should adopt differentiated CLC strategies. The main urban area should focus on ecological spatial governance and agricultural modernization infrastructure; the northeastern region should strengthen public service infrastructure and improve production and living pollution treatment facilities; and the southeastern region should moderately concentrate the population and improve the efficiency of services, as well as protect and excavate the cultures of ethnic minorities.

Background: Metastasis is the primary cause of lung cancer-related death. Primary cancer cells invade through the lymphatic or blood vessels to distant sites. Recently, it was proposed that lymphatic metastasis was more a hallmark of tumor aggressiveness or metastatic potential than a gateway to metastases. Therefore, the underlying molecular mechanism of metastasis is not entirely clear. Objectives: This study aimed to explore the genetic mechanisms underlying liver metastases from lung cancer and to evaluate the efficacy of different therapies in these patients. Design: We retrospectively analyzed the mutation spectrum of different biopsy samples including primary lung tumors, liver, lymph node metastasis, and circulating tumor DNA (ctDNA) from 1090 non-small-cell lung cancer (NSCLC) patients with liver metastasis between the years 2017 and 2022. Methods: Demographic and disease characteristics were summarized using descriptive parameters. Time to treatment discontinuation was used to analyze the clinical outcome. Results: More liquid biopsies were performed than tissue biopsies, especially in the treated advanced NSCLC patients. Liver metastasis before treatment was associated with poor response to immune checkpoint inhibitors and targeted therapy. Liver and lymph node metastasis had higher levels of single nucleotide variants and copy number variants than primary lung tumors. In paired lung and liver, lymph nodes, and simultaneous ctDNA, we found actionable mutations were always shared, while metastasis samples had multiple private mutations. Serial ctDNA analysis identifies potential resistant mutations and describes the evolution of tumor cells. Conclusion: Liver and lymph node metastasis in NSCLC showed shared actionable mutations. Of note, the discrepancy of private mutations in liver and lymph node metastases indicated that liver metastases are mainly seeded by the primary tumor rather than the earlier colonized lymph node metastases.

Abstract Background Circulating tumor DNA (ctDNA) has emerged as a potential novel biomarker to predict molecular residual disease (MRD) in lung cancer after definitive treatment. Herein, we investigated the value of ctDNA in prognosing risk of relapse and monitoring the effect of adjuvant therapy in surgical non‐small cell lung cancer (NSCLC). Methods We enrolled 58 NSCLC patients in a real‐world setting, and 58 tumor tissues and 325 plasma samples were analyzed. Tumor tissues and plasma samples were subjected to targeted next‐generation sequencing (NGS) of 1021 cancer‐related and ultra‐deep targeted NGS covering 338 genes, respectively. Results ctDNA was detected in 31.0% of cases at the first postoperative time, which was associated with advanced tumor stage, T stage and KEAP1 or GRIN2A mutations in tissues. ctDNA positivity at landmark and longitudinal indicated the shorter disease‐free survival. For patients with ctDNA positivity at the first postoperative time, regardless of adjuvant therapy, all patients who were persistently ctDNA positive during postoperative surveillance had disease recurrence. Among the patients who were ctDNA negative, only two patients (15.4%, 2/13) receiving adjuvant therapy relapsed, while one patient (50.0%, 1/2) without adjuvant therapy relapsed. For the first postoperative ctDNA negative patients, the recurrence rate of patients with adjuvant therapy was and higher than without adjuvant therapy (22.6% [7/31] vs. 11.1% [1/9]). The patients who became ctDNA positive may also benefit from intervention therapy. Conclusion Postoperative ctDNA is a prognostic marker, and ctDNA‐detection may facilitate personalized adjuvant therapy, and applying adjuvant therapy to the patients with detectable ctDNA could bring clinical benefits for them.

Abstract Background Heart failure (HF) is a disease that poses a serious threat to individual health, and DNA methylation is an important mechanism in epigenetics, and its role in the occurrence and development of the disease has attracted more and more attention. The aim of this study was to evaluate the link between iodothyronine deiodinase 3 promoter region fragment FA27 (DIO3-FA27) methylation levels, biochemical indices, and HF. Results The methylation levels of DIO3-FA27_CpG_11.12 and DIO3-FA27_CpG_23.24 significantly differed in HF patients with different degrees. Multivariate logistic regression analysis indicated that the relative HF risk in the third and fourth quartiles of activated partial thromboplastin time and fibrin degradation products. The results of the restricted cubic spline model showed that the methylation levels of DIO3-FA 27_CpG_11.12 and DIO3-FA 27_CpG_23.24 were associated with coagulation indicators, liver function, renal function, and blood routine. Conclusions Based on the differential analysis of CpG methylation levels based on DIO3-FA27, it was found that biochemical indicators combined with DIO3-FA27 promoter DNA methylation levels could increase the risk of worsening the severity classification of HF patients, which provided a solid foundation and new insights for the study of epigenetic regulation mechanisms in patients with HF.

Abstract Exercise is a potential treatment to improve sleep quality in middle-aged and elderly individuals. Understanding exercise-induced changes in functional plasticity of brain circuits that underlie improvements in sleep among middle-aged and older adults can inform treatment of sleep problems. The aim of the study is to identify the effects of a 12-week exercise program on sleep quality and brain functional connectivity in middle-aged and older adults with insomnia. The trial was registered with Chinese Clinical Trial Register (ChiCTR2000033652). We recruited 84 healthy sleepers and 85 individuals with insomnia. Participants with insomnia were assigned to receive either a 12-week exercise intervention or were placed in a 12-week waitlist control condition. Thirty-seven middle-aged and older adults in the exercise group and 30 in the waitlist group completed both baseline and week 12 assessments. We found that middle-aged and older adults with insomnia showed significantly worse sleep quality than healthy sleepers. At the brain circuit level, insomnia patients showed decreased connectivity in the widespread motor network. After exercise intervention, self-reported sleep was increased in the exercise group (P

BackgroundIntravaginal electrical stimulation (IVES) has been explored as a potential treatment for pelvic floor disorders (PFDs), although its efficacy remains a subject of debate. We aim to conducted a comprehensive meta-analysis of relevant trials.MethodsThis meta-analysis was performed under the PRISMA 2020 guideline. We meticulously searched for randomized controlled trial (RCT) studies in various databases, including PubMed, Cochrane Library, EMBASE, and ClinicalTrials.gov, spanning from inception to March 6, 2023. All studies included one treatment group of intravaginal electrical stimulation and the diseases spectrum of the studies involved different kinds of PFDs, including urinary incontinence, overactive bladder, etc. Risk of bias charts were used to assess the risk of bias in the studies and forest plots were used the demonstrate the overall effects.ResultsOur analysis encompassed a total of 13 RCT studies. In most of the assessed PFD cure outcomes, the results demonstrated positive effects of IVES therapy, as indicated by the following findings: daily voiding frequency (MD = −1.57, 95% CI = −3.08 to −0.06, I2 = 68%,), nocturia (MD = −1.07, 95% CI = −2.01 to −0.13, I2 = 71%), Pad test, and Urinary incontinence. Nevertheless, the data concerning the impact of IVES therapy on the quality of life of individuals with PFDs did not confirm these positive results.DiscussionIn light of the insufficiency in both the quality and quantity of the included studies, it is premature to draw a definitive conclusion regarding the efficacy of IVES therapy for treating PFDs. Nonetheless, our study does provide several pieces of evidence in support of the potential therapeutic effects of electrical stimulation therapy in this context. We recommend that further research in this area be conducted to provide more conclusive insights into the efficacy of IVES therapy for PFDs.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier: CRD42023442171.

Patients with the target gene mutation frequently derive significant clinical benefits from target therapy. However, differences in the abundance level of mutations among patients resulted in varying survival benefits, even among patients with the same target gene mutations. Currently, there is a lack of rational and interpretable models to assess the risk of treatment failure. In this study, we investigated the underlying coupled factors contributing to variations in medication sensitivity and established a statistically interpretable framework, named SAFE-MIL, for risk estimation. We first constructed an effectiveness label for each patient from the perspective of exploring the optimal grouping of patients’ positive judgment values and sampled patients into 600 and 1,000 groups, respectively, based on multi-instance learning (MIL). A novel and interpretable loss function was further designed based on the Hosmer-Lemeshow test for this framework. By integrating multi-instance learning with the Hosmer-Lemeshow test, SAFE-MIL is capable of accurately estimating the risk of drug treatment failure across diverse patient cohorts and providing the optimal threshold for assessing the risk stratification simultaneously. We conducted a comprehensive case study involving 457 non-small cell lung cancer patients with EGFR mutations treated with EGFR tyrosine kinase inhibitors. Results demonstrate that SAFE-MIL outperforms traditional regression methods with higher accuracy and can accurately assess patients’ risk stratification. This underscores its ability to accurately capture inter-patient variability in risk while providing statistical interpretability. SAFE-MIL is able to effectively guide clinical decision-making regarding the use of drugs in targeted therapy and provides an interpretable computational framework for other patient stratification problems. The SAFE-MIL framework has proven its effectiveness in capturing inter-patient variability in risk and providing statistical interpretability. It outperforms traditional regression methods and can effectively guide clinical decision-making in the use of drugs for targeted therapy. SAFE-MIL offers a valuable interpretable computational framework that can be applied to other patient stratification problems, enhancing the precision of risk assessment in personalized medicine. The source code for SAFE-MIL is available for further exploration and application at https://github.com/Nevermore233/SAFE-MIL.

Pathogenic bacteria's metabolic adaptation for survival and proliferation within hosts is a crucial aspect of bacterial pathogenesis. Here, we demonstrate that citrate, the first intermediate of the tricarboxylic acid (TCA) cycle, plays a key role as a regulator of gene expression in Staphylococcus aureus. We show that citrate activates the transcriptional regulator CcpE and thus modulates the expression of numerous genes involved in key cellular pathways such as central carbon metabolism, iron uptake and the synthesis and export of virulence factors. Citrate can also suppress the transcriptional regulatory activity of ferric uptake regulator. Moreover, we determined that accumulated intracellular citrate, partly through the activation of CcpE, decreases the pathogenic potential of S. aureus in animal infection models. Therefore, citrate plays a pivotal role in coordinating carbon metabolism, iron homeostasis, and bacterial pathogenicity at the transcriptional level in S. aureus, going beyond its established role as a TCA cycle intermediate.

Abstract The network structure of digital watermarking algorithm based on deep learning is usually encoder‐noise layer‐decoder. Most of the existing encoders suffer from the problem of insufficient feature extraction, and the introduction of simulated differentiable joint photographic experts group (JPEG) compression in the noise layer cannot ensure the robustness under real JPEG. In this paper, a watermarking algorithm based on multi‐scale auto‐encoder is proposed, which can effectively extract the image feature information by combining with the channel attention mechanism. At the same time, some parameters of decoder and encoder are shared to reduce redundant feature embedding and improve extraction accuracy. This paper also proposes a robust training scheme against JPEG compression, which can guide the model to store the watermark in the low‐frequency region needed for decoding. Experimental results show that the peak signal‐to‐noise ratio (PSNR) of the proposed algorithm is above 48 and the decoding rate is above 99% under JPEG compression with quality factor Q = 50. Moreover, this scheme can effectively promote the combination of noise layer in training. In addition, the proposed algorithm is also robust to other common network noises.

Abstract Background The U-box gene family encodes E3 ubiquitin ligases involved in plant hormone signaling pathways and abiotic stress responses. However, there has yet to be a comprehensive analysis of the U-box gene family in maize (Zea mays L.) and its responses to abiotic stress. Results In this study, 85 U-box family proteins were identified in maize and were classified into four subfamilies based on phylogenetic analysis. In addition to the conserved U-box domain, we identified additional functional domains, including Pkinase, ARM, KAP and Tyr domains, by analyzing the conserved motifs and gene structures. Chromosomal localization and collinearity analysis revealed that gene duplications may have contributed to the expansion and evolution of the U-box gene family. GO annotation and KEGG pathway enrichment analysis identified a total of 105 GO terms and 21 KEGG pathways that were notably enriched, including ubiquitin-protein transferase activity, ubiquitin conjugating enzyme activity and ubiquitin-mediated proteolysis pathway. Tissue expression analysis showed that some ZmPUB genes were specifically expressed in certain tissues and that this could be due to their functions. In addition, RNA-seq data for maize seedlings under salt stress revealed 16 stress-inducible plant U-box genes, of which 10 genes were upregulated and 6 genes were downregulated. The qRT-PCR results for genes responding to abiotic stress were consistent with the transcriptome analysis. Among them, ZmPUB13, ZmPUB18, ZmPUB19 and ZmPUB68 were upregulated under all three abiotic stress conditions. Subcellular localization analysis showed that ZmPUB19 and ZmPUB59 were located in the nucleus. Conclusions Overall, our study provides a comprehensive analysis of the U-box gene family in maize and its responses to abiotic stress, suggesting that U-box genes play an important role in the stress response and providing insights into the regulatory mechanisms underlying the response to abiotic stress in maize.

In the field of autonomous driving, common challenges include difficulties in detecting small vehicles and pedestrians on the road, high computational demands of algorithms, and low accuracy of detection algorithms. This paper proposes a YOLOv8n-FAWL object detection algorithm tailored for edge computing, incorporating the following three improvements: (1) The Faster-C2f-EMA module is created, designed through the synergy of the FasterNet architecture and the concept of EMA modules, effectively addressing the challenge of suboptimal feature extraction for small objects. (2) The WIOU loss function is adopted to resolve the issue of imbalanced training samples. (3) The LAMP pruning technique is applied to reduce the model parameters and complexity, thereby enhancing the overall model accuracy. The experimental results show that compared to the baseline model, the proposed algorithm achieves improvements of 6.2% and 4.5% in the mAP@0.5, and 3.8% and 2.7% in the mAP@0.5:0.95, on the Udacity and BDD100K-tiny datasets,respectively. In addition, the model parameters we’re reduced by 49.2% and 46%. The model achieved real-time performance at 54 FPS, thereby advancing the development of autonomous driving technology.

Abstract Background The association between air pollution and retinal diseases such as age-related macular degeneration (AMD) has been demonstrated, but the pathogenic correlation is unknown. Damage to the outer blood–retinal barrier (oBRB), which consists of the retinal pigment epithelium (RPE) and choriocapillaris, is crucial in the development of fundus diseases. Objectives To describe the effects of airborne fine particulate matter (PM2.5) on the oBRB and disease susceptibilities. Methods A PM2.5-exposed mice model was established through the administration of eye drops containing PM2.5. Optical coherence tomography angiography, transmission electron microscope, RPE immunofluorescence staining and Western blotting were applied to study the oBRB changes. A co-culture model of ARPE-19 cells with stretching vascular endothelial cells was established to identify the role of choroidal vasodilatation in PM2.5-associated RPE damage. Results Acute exposure to PM2.5 resulted in choroidal vasodilatation, RPE tight junctions impairment, and ultimately an increased risk of retinal edema in mice. These manifestations are very similar to the pachychoroid disease represented by central serous chorioretinopathy (CSC). After continuous PM2.5 exposure, the damage to the RPE was gradually repaired, but AMD-related early retinal degenerative changes appeared under continuous choroidal inflammation. Conclusion This study reveals oBRB pathological changes under different exposure durations, providing a valuable reference for the prevention of PM2.5-related fundus diseases and public health policy formulation. Graphical abstract

As mental health issues become increasingly prominent, we are now facing challenges such as the severe unequal distribution of medical resources and low diagnostic efficiency. This paper integrates finite state machines, retrieval algorithms, semantic-matching models, and medical-knowledge graphs to design an innovative intelligent auxiliary evaluation tool and a personalized medical-advice generation application, aiming to improve the efficiency of mental health assessments and the provision of personalized medical advice. The main contributions include the folowing: (1) Developing an auxiliary diagnostic tool that combines the Mini-International Neuropsychiatric Interview (M.I.N.I.) with finite state machines to systematically collect patient information for preliminary assessments; (2) Enhancing data processing by optimizing retrieval algorithms for efficient filtering and employing a fine-tuned RoBERTa model for deep semantic matching and analysis, ensuring accurate and personalized medical-advice generation; (3) Generating intelligent suggestions using NLP techniques; when semantic matching falls below a specific threshold, integrating medical-knowledge graphs to produce general medical advice. Experimental results show that this application achieves a semantic-matching degree of 0.9 and an accuracy of 0.87, significantly improving assessment accuracy and the ability to generate personalized medical advice. This optimizes the allocation of medical resources, enhances diagnostic efficiency, and provides a reference for advancing mental health care through artificial-intelligence technology.

Abstract Background & aims This study aims to assess the nutritional status of patients during the different phases of the Chimeric Antigen Receptor (CAR)-T cell therapy and to identify prominent risk factors of hypoalbuminemia in patients after CAR-T treatment. The clinical consequences of malnutrition in cancer patients have been highlighted by growing evidence from previous clinical studies. Given CAR-T cell therapy's treatment intensity and possible side effects, it is important to provide patients with sufficient medical attention and support for their nutritional well-being. Methods This study was conducted from May 2021 to December 2021 among patients undergoing CAR-T cell therapy at the Bone Marrow Transplantation Center in The First Affiliated Hospital of Zhejiang University School of Medicine. Logistic regression analysis was performed to investigate the risk factors associated with hypoalbuminemia. Participants were divided into the cytokine release syndrome (CRS) group (n = 60) and the non-CRS group (n = 11) to further analyze the relationship between hypoalbuminemia and CRS. Results CRS (OR = 13.618; 95% CI = 1.499–123.709; P = 0.013) and baseline albumin (ALB) (OR = 0.854; 95% CI = 0.754–0.967; P = 0.020) were identified as the independent clinical factors associated with post-CAR-T hypoalbuminemia. According to the nadir of serum albumin, hypoalbuminemia occurred most frequently in patients with severe CRS (78.57%). The nadir of serum albumin (r = − 0.587, P

Abstract Osteosarcoma is a heterogeneous disease with regard to its chemotherapy response and clinical outcomes. This study aims to investigate the genomic and transcriptomic characteristics related to pre-operative chemotherapy response. Samples from 25 osteosarcoma patients were collected to perform both whole exome and transcriptome sequencing. Osteosarcoma had significant amount of chromosomal copy number variants (CNVs). Chemotherapy responders showed the higher chromosomal CNV burden than non-responders (p = 0.0775), but the difference was not significant. The percentage of COSMIC signature 3, associated with homologous recombination repair deficiency, was higher in responders (56%) than in non-responders (45%). Transcriptomic analysis suggested that 11 genes were significantly up-regulated in responders and 18 genes were up-regulated in non-responders. Both GSEA and KEGG enrichment analysis indicted that four pathways related to cardiomyopathy were up-regulated in responders, while neuroactive ligand − receptor interaction was up-regulated in non-responders. Finally, a previously published chemoresistant model was validated using our dataset, with the area under the curve of 0.796 (95% CI, 0.583–1.000). Osteosarcoma had the heterogeneous mutational profile with frequent occurrence of CNVs. Transcriptomic analysis identified several signaling pathways associated with chemotherapy responsiveness to osteosarcoma. Transcriptomic signatures provides a potential research direction for predicting the chemotherapy response.

Although several pentatricopeptide repeat (PPR) proteins are involved in post-transcriptional processing of mitochondrial RNA, it is unclear which specific protein is involved in the RNA editing of ccmC in maize (Zea mays). Here we report the identification of the maize empty pericarp 601 (emp601) mutant and the map-based cloning of the Emp601 gene, which encodes an E2-type PPR protein that is targeted to mitochondria. A single-nucleotide deletion in the emp601 mutant caused a frameshift and introduced a premature stop codon into the predicted EMP601. This mutation was associated with reduced accumulation of mitochondrial complex III as well as with inhibition of growth and differentiation of basal endosperm transfer layer cells, leading to final degeneration of the embryo and endosperm. We determine that loss of EMP601 function prevents the C-to-U RNA editing of the mitochondrial transcript ccmC at position 358. EMP601 binds to the ccmC transcript and directly interacts with Multiple organellar RNA editing factor 8 and may be a component of the plant mitochondrial editosome. We conclude that EMP601 functions in RNA editing of mitochondrial ccmC transcripts and influences mitochondrial function and seed development.

The uptake of ammonium, nitrate, phosphorus, and potassium ions by roots is mediated by specific ion transporter or channel proteins, and protein phosphorylation regulation events occurring on these proteins and their regulators determine their ultimate activity. Elucidating the mechanism by which protein phosphorylation modification regulates nutrient uptake will advance plant breeding for high nutrient-use efficiency. In this review, it is concluded that the root nutrient absorption system is composed of several, but not all, members of a specific ion transporter or channel family. Under nutrient-starvation conditions, protein phosphorylation-based regulation of these proteins and associated transcription factors increases ion transporter- or channel-mediated nutrient uptake capacity via direct function activity enhancement, allowing more protein trafficking to the plasma membrane, by strengthening the interaction of transporters and channels with partner proteins, by increasing their protein stability, and by transcriptional activation. Under excessive nutrient conditions, protein phosphorylation-based regulation suppresses nutrient uptake by reversing these processes. Strengthening phosphorylation regulation items that increase nutrient absorption and weakening phosphorylation modification items that are not conducive to nutrient absorption show potential as strategies for increasing nutrient use efficiency.

Abstract Background Pulmonary hypertension (PH) is a lethal vascular disease with limited therapeutic options. The mechanistic connections between alveolar hypoxia and PH are not well understood. The aim of this study was to investigate the role of mitotic regulator Polo-like kinase 1 (PLK1) in PH development. Methods Mouse lungs along with human pulmonary arterial smooth muscle cells and endothelial cells were used to investigate the effects of hypoxia on PLK1. Hypoxia- or Sugen5416/hypoxia was applied to induce PH in mice. Plk1 heterozygous knockout mice and PLK1 inhibitors (BI 2536 and BI 6727)-treated mice were checked for the significance of PLK1 in the development of PH. Results Hypoxia stimulated PLK1 expression through induction of HIF1α and RELA. Mice with heterozygous deletion of Plk1 were partially resistant to hypoxia-induced PH. PLK1 inhibitors ameliorated PH in mice. Conclusions Augmented PLK1 is essential for the development of PH and is a druggable target for PH.

The utilization of a nanoporous (NP) GaN fabricated by electrochemical etching has been demonstrated to be effective in the fabrication of a high-performance ultraviolet (UV) photodetector (PD). However, the NP-GaN PD typically exhibits a low light-dark current ratio and slow light response speed. In this study, we present three types of UV PDs based on an unetched GaN, NP-GaN distributed Bragg reflector (DBR), and NP-GaN-DBR with a Ga2O3 single-crystal film (Ga2O3/NP-GaN-DBR). The unetched GaN PD does not exhibit a significant photoresponse. Compared to the NP-GaN-DBR PD device, the Ga2O3/NP-GaN-DBR PD demonstrates a larger light-dark current ratio (6.14 × 103) and higher specific detectivity (8.9 × 1010 Jones) under 365 nm at 5 V bias due to its lower dark current (3.0 × 10−10 A). This reduction in the dark current can be attributed to the insertion of the insulating Ga2O3 between the metal and the NP-GaN-DBR, which provides a thicker barrier thickness and higher barrier height. Additionally, the Ga2O3/NP-GaN-DBR PD device exhibits shorter rise/decay times (0.33/0.23 s) than the NP-GaN-DBR PD, indicating that the growth of a Ga2O3 layer on the DBR effectively reduces the trap density within the NP-GaN DBR structure. Although the device with a Ga2O3 layer presents low photoresponsivity (0.1 A/W), it should be feasible to use Ga2O3 as a dielectric layer based on the above-mentioned reasons.

The search for room-temperature superconductors has been a long-standing goal in condensed matter physics. In this study, we investigate the electronic and geometric properties of lead apatite with and without Cu doping within the framework of the density functional theory. Based on our calculations, we found that without Cu doping, the lead apatite PPOO shows an insulator character with flatbands that straddle the Fermi level. Once we introduce O1 vacancies, the flatbands disappear. Furthermore, we analyze the effects of Cu doping on the crystal structure and the electronic band structure of the material PCPOO4. Our calculations reveal the presence of one-dimensional channels induced by fully occupied O1 atoms that are only 1/4 occupied in the literature, which may play a crucial role in the realization of room-temperature superconductivity. Based on our findings, we propose a possible solution to improve the quality of superconductivity by annealing the material in an oxygen atmosphere. These results contribute to a better understanding of the unusual properties of Cu-doped lead apatite PCPOO4 and will pave the way for further exploration of its potential as a room-temperature superconductor.

Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory disease characterized by familial and acquired forms. Here, we present the case of a 26-year-old male patient with relapsed/refractory peripheral T-cell lymphoma and concurrent HLH. Whole-exon sequencing revealed germline mutations associated with HLH, including those in critical genes such as CD27 and UNC13D and other germline heterozygous variants ( NOTCH2, NOTCH3, IL2RA, TYK2, AGL, CFD , and F13A1 ). CD107a analyses consistently demonstrated impaired degranulation of cytotoxic T-lymphocytes and natural killer (NK) cells. Examination of the patient’s family pedigree revealed that his father and mother harbored UNC13D and CD27 mutations, respectively; his brother carried the same CD27 heterozygous mutation. However, none of them manifested the disease. Despite the missense mutation of CD27 (c.779C>T; p.Pro260Leu) lacking previous documentation in databases, comprehensive analysis suggested non-pathogenic mutations in the CD27 variant, indicating minimal impact on T- and NK-cell functions. These results ultimately supported the option of hematopoietic stem cell transplantation (HSCT) as a successful curative therapeutic approach. As of this report, the patient has remained free of lymphoma and quiescent HLH 15.2 months post-HSCT. This study underscores the efficacy of genetic tests in identifying significant mutations and confirming their etiologies, providing an early basis for treatment decisions and the selection of suitable transplant donors.

Background: Circulating tumor DNA (ctDNA) has emerged as a biomarker that can define the risk of recurrence after curative-intent surgery for patients with colorectal cancer (CRC). However, beyond the predictive power of postoperative ctDNA detection, the efficacy and potential limitations of ctDNA detection urgently need to be fully elucidated in a large cohort of CRC. Objectives: To define potentially cured CRC patients through ctDNA monitoring following surgery. Design: A prospective, multicenter, observational study. Methods: We enrolled 309 patients with stages I–IV CRC who underwent definitive surgery. Tumor tissues were sequenced by a custom-designed next-generation sequencing panel to identify somatic mutations. Plasma was analyzed using a ctDNA-based molecular residual disease (MRD) assay which integrated tumor-genotype-informed and tumor-genotype-naïve ctDNA analysis. The turnaround time of the assay was 10–14 days. Results: Postoperative ctDNA was detected in 5.4%, 13.8%, 15%, and 30% of patients with stage I, II, III, and IV disease, respectively, and in 17.5% of all longitudinal samples. Patients with positive postsurgery MRD had a higher recurrence rate than those with negative postsurgery MRD [hazard ratio (HR), 13.17; p < 0.0001], producing a sensitivity of 64.6%, a specificity of 94.8%, a positive predictive value (PPV) of 75.6%, and a negative predictive value (NPV) of 91.5%. Furthermore, patients with positive longitudinal MRD also had a significantly higher recurrence rate (HR, 14.44; p < 0.0001), with increased sensitivity (75.0%), specificity (94.9%), PPV (79.6%), and NPV (93.4%). Subgroup analyses revealed that adjuvant therapy did not confer superior survival for patients with undetectable or detectable MRD. In addition, MRD detection was less effective in identifying lung-only and peritoneal metastases. Conclusion: Postoperative ctDNA status is a strong predictor of recurrence independent of stage and microsatellite instability status. Longitudinal undetectable MRD could be used to define the potentially cured population in CRC patients undergoing curative-intent surgery.

The pantograph is one of the primary sources of aerodynamic drag and noise during the operation of a high-speed train. To investigate the impact of the pantograph fairing on the aerodynamic performance at various train heights, six computational models are established, and the Improved Delayed Detached Eddy Simulation method is employed. The results indicate that the installation of the fairing can effectively reduce the aerodynamic drag coefficient of the high-speed train and pantograph at different train heights. As the train height increases, the drag reduction effect of the fairing enhances when the sinking platform coexists. The overall drag reduction rate of up to 4.30% can be achieved at a train height of 4000 mm. However, the larger reduction rate of 58.32% in the pantograph's drag coefficient at a train height of 3700 mm indicates that the fairing could make a greater effect on the pantograph at a smaller train height. The reduction in train height and pantograph sinking height leads to an increase in drag coefficient on the tail car, and the implementation of the fairing further amplifies the drag. This work offers a reference for optimizing the aerodynamic performance of high-speed train.

ABSTRACTIn many Gram-positive bacteria, the transpeptidase enzyme sortase A (SrtA) anchors surface proteins to cell wall and plays a critical role in the bacterial pathogenesis. Here, we show that in Staphylococcus aureus, an important human pathogen, the SrtA is phosphorylated by serine/threonine protein kinase Stk1. S. aureus SrtA can also be phosphorylated by small-molecule phosphodonor acetyl phosphate (AcP) in vitro. We determined that various amino acid residues of S. aureus SrtA are subject to phosphorylation, primarily on its catalytic site residue cysteine-184 in the context of a bacterial cell lysate. Both Stk1 and AcP-mediated phosphorylation inhibited the enzyme activity of SrtA in vitro. Consequently, deletion of gene (i.e. stp1) encoding serine/threonine phosphatase Stp1, the corresponding phosphatase of Stk1, caused an increase in the phosphorylation level of SrtA. The stp1 deletion mutant mimicked the phenotypic traits of srtA deletion mutant (i.e. attenuated growth where either haemoglobin or haem as a sole iron source and reduced liver infections in a mouse model of systemic infection). Importantly, the phenotypic defects of the stp1 deletion mutant can be alleviated by overexpressing srtA. Taken together, our finding suggests that phosphorylation plays an important role in modulating the activity of SrtA in S. aureus.

Circulating tumor DNA (ctDNA) has potential as a promising biomarker for molecular residual disease (MRD) detection in lung cancer. As the next‐generation sequencing standardized panel for ctDNA detection emerges, its clinical utility needs to be validated. We prospectively recruited 184 resectable lung cancer patients from four medical centers. Serial postoperative ctDNAs were analyzed by a standardized panel. A total of 427 postoperative plasma samples from 177 eligible patients were enrolled. ctDNA positivity after surgery was an independent predictor for disease recurrence and preceded radiological recurrence by a median of 6.6 months (range, 0.7–27.0 months). ctDNA‐positive or ‐negative patients with tumors of any stage had similar disease‐free survival (DFS). Patients who received targeted therapy had significantly improved DFS than those not receiving adjuvant therapy or receiving chemotherapy, regardless of baseline/preadjuvant ctDNA status. According to whether the ctDNA variants were detected in its matched tissue, they were classified into tissue derived and non‐tissue derived. Patients with detectable postoperative ctDNA with tissue‐derived mutations had comparable DFS with those with non‐tissue‐derived mutations. Collectively, we demonstrated that postoperative ctDNA has the potential to stratify prognosis and optimize tumor stage in resectable lung cancer. ctDNA variants not identified in tissue samples should be considered in MRD test.

Abstract Background The previous studies have revealed that abnormal RNA-binding protein Musashi-2 (MSI2) expression is associated with cancer progression through post-transcriptional mechanisms, however mechanistic details of this regulation in acute myeloid leukemia (AML) still remain unclear. Our study aimed to explore the relationship between microRNA-143 (miR-143) and MSI2 and to clarify their clinical significance, biological function and mechanism. Methods Abnormal expression of miR-143 and MSI2 were evaluated in bone marrow samples from AML patients by quantitative real time-PCR. Effects of miR-143 on regulating MSI2 expression were investigated using luciferase reporter assay. Functional roles of MSI2 and miR-143 on AML cell proliferation and migration were determined by CCK-8 assay, colony formation, and transwell assays in vitro and in mouse subcutaneous xenograft and orthotopic transplantation models in vivo. RNA immunoprecipitation, RNA stability measurement and Western blotting were performed to assess the effects of MSI2 on AML. Results We found that MSI2 was significantly overexpressed in AML and exerted its role of promoting AML cell growth by targeting DLL1 and thereby activating Notch signaling pathway. Moreover, we found that MSI2 bound to Snail1 transcript and inhibited its degradation, which in turn upregulated the expression of matrix metalloproteinases. We also found that MSI2 targeting miR-143 is downregulated in AML. In the AML xenograft mouse model, overexpression of MSI2 recapitulated its leukemia-promoting effects, and overexpression of miR-143 partially attenuated tumor growth and prevented metastasis. Notably, low expression of miR-143, and high expression of MSI2 were associated with poor prognosis in AML patients. Conclusions Our data demonstrate that MSI2 exerts its malignant properties via DLL1/Notch1 cascade and the Snail1/MMPs axes in AML, and upregulation of miR-143 may be a potential therapeutic approach for AML.

Heterosis and polyploidy have an overwhelming influence on plant evolution. Recently, polyploid rice hybrids have been used to breed new rice varieties because they combine the advantages of both heterosis and polyploidy. In this study, we generated six rice lines: autotetraploid rice hybrids and their autotetraploid parents, diploid donors, and hybrids of the diploid donors. To investigate the molecular mechanism controlling the effects of both hybridization and polyploidization, we performed bisulfite and RNA sequencing on young panicles at the pollen meiosis stage to compare the DNA metabolomes and transcriptomes among the six rice lines. The hybrids lines were hypermethylated compared to their corresponding parents and the autotetraploid lines showed globally increased DNA methylation of their transposable elements compared to the diploid donors. The alteration in DNA methylation level corresponded to the differential gene expressions among the rice genotypes, suggesting that methylation changes induced by polyploidization and hybridization may affect gene expression. Groups of gene candidates were identified that may be associated with heterosis and polyploidy. Our results provide DNA information that can be used to investigate epigenetic modification during heterosis and polyploidy in rice.

The two-component regulatory system VraRS regulates transcription of penicillin-binding protein 2 in response to cell wall antimicrobials. Here, Lu et al. show that an enzyme from the wall teichoic acid biosynthetic pathway of MRSA can also modulate the expression of virulence factors such as Staphylococcal protein A via VraRS.

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.

Abstract Objectives In order to explore the impact of pegylated liposomal doxorubicin (PLD) dose intensity on survival outcomes of newly diagnosed elderly patients with diffuse large B‐cell lymphoma (DLBCL), we performed a retrospective study to compare the efficacy and adverse effects of RCEOP (70 mg/m2), RCdOP (20–30 mg/m2) and RCDOP (30–45 mg/m2). The optimal PLD dose of patients with different clinical characteristics of subgroups was explored to provide a clue for the selection of clinical PLD dose. Methods A total of 335 DLBCL patients (60–85 years old) who were newly diagnosed and completed at least four cycles of RCE(D)OP were selected. The patients were mainly divided into RCEOP (126 cases) (epirubicin 70 mg/m2), RCdOP (151 cases) (PLD 20–30 mg/m2) and RCdOP (58 cases) (PLD 30–45 mg/m2). The effects of different doses of PLD on clinical efficacy, cardiotoxicity and prognosis of patients were retrospectively analyzed. Subgroup analysis was performed to compare the clinical characteristics of different subgroups. Results Our study showed that PLD and epirubicin had similar efficacy (overall survival (OS) p = 0.776; progression‐free survival (PFS) p = 0.959). RCDOP (30–45 mg/m2 PLD) group had a higher complete remission (CR) rate of 75.9% compared with RCdOP (20–30 mg/m2 PLD) group (P D vs. d = 0.018). In the overall population, there was no significant difference in survival between RCDOP and RCdOP groups (OS P D vs. d = 0.661; PFS P D vs. d = 0.212). In patients with underlying cardiovascular diseases, the PFS of the RCDOP group was significantly better than the RCdOP group (p = 0.043). Meanwhile, patients in the RCDOP group tended to have a better prognosis than those in the RCEOP group (OS: RCDOP vs. RCEOP p = 0.054, PFS: RCDOP vs. RCEOP p = 0.053). There was no significant difference in the incidence of cardiotoxicity and other adverse events among the three groups. For the low‐risk (age‐adjusted‐International Prognostic Index = 0/1) old patients without cardiovascular disease, RCdOP was considered a better strategy in OS (p = 0.020). Conclusion In the general population, the CR rate in the RCDOP group was significantly higher than that in the RCdOP group (p = 0.018). For elderly DLBCL patients with cardiovascular disease, the effect benefit brought by the PLD dose was more obvious, and the PFS of the RCDOP group was significantly better than that of the RCdOP group (p = 0.043). Full dose of PLD is an efficient alternative in the treatment of patients with preexisting cardiovascular diseases.

Background Acute myeloid leukemia (AML) with t(8;21) is generally associated with a favorable clinical course. Loss of sex chromosome (LOS) are frequently observed in t (8;21) AML, but the prognostic value of LOS remains uncertain.Methods A total of 73 patients with AML with t(8;21) were studied and divided into t(8;21) with LOS group (n = 36) and t(8;21) alone group (n = 37). The patients with t(8;21) AML with ACAs other than LOS were excluded. The clinical characteristics of these two groups were compared, and the prognostic value of LOS was evaluated based on disease-free survival (DFS) and overall survival (OS).Results The clinical characteristics (except for gender) were found to have no significant difference between these two groups, and the male patients tended to account for a larger proportion in the former group (P = .001). The OS of the t(8;21) AML with LOS group was significantly longer than that of the t(8;21) AML alone group (P = .005). While not obvious, the patients with LOS seemed to have longer DFS (P = .061). The multivariable analysis also showed LOS to be an independent favorable prognostic factor of t(8;21) AML (P = .022).Conclusions Our results suggested that LOS could be associated with a favorable prognosis in t(8;21) AML patients without other ACAs, and for this subtype of AML, longer DFS and a satisfactory and stable survival can be achieved with high-dose cytarabine (HDAC) consolidation treatment.

This study was carried out to investigate the effects of probiotics and Chinese medicine polysaccharides (CMP) on carcase characteristics, meat quality, muscle fibre type and intramuscular fat deposition in lambs. Forty female lambs with 4-5 months old and 21.69 ± 0.46 kg were randomly divided into four groups as follows: control, probiotics, CMP and probiotics + CMP groups. The results showed that supplemental probiotics increased carcase yield, the percentage of abdominal fat and perirenal fat of lambs, the levels of moisture and intramuscular fat in Longissimus thoracis (LT) muscle and the mRNA expression of MyHC I but decreased the value of shear force, lightness (L*) and yellowness (b*) and the percentage of heneicosanoic acid (C21:0) in LT muscle compared with the control group (p

Tillering directly determines the seed production and propagation capacity of clonal plants. However, the molecular mechanisms involved in the tiller development of clonal plants are still not fully understood. In this study, we conducted a proteome comparison between the tiller buds and stem node of a multiple-tiller mutant mtn1 (more tillering number 1) and a wild type of centipedegrass. The results showed significant increases of 29.03% and 27.89% in the first and secondary tiller numbers, respectively, in the mtn1 mutant compared to the wild type. The photosynthetic rate increased by 31.44%, while the starch, soluble sugar, and sucrose contents in the tiller buds and stem node showed increases of 13.79%, 39.10%, 97.64%, 37.97%, 55.64%, and 7.68%, respectively, compared to the wild type. Two groups comprising 438 and 589 protein species, respectively, were differentially accumulated in the tiller buds and stem node in the mtn1 mutant. Consistent with the physiological characteristics, sucrose and starch metabolism as well as plant hormone signaling were found to be enriched with differentially abundant proteins (DAPs) in the mtn1 mutant. These results revealed that sugars and plant hormones may play important regulatory roles in the tiller development in centipedegrass. These results expanded our understanding of tiller development in clonal plants.

As one of the most salt-tolerant grasses, characterizing salt-tolerance genes of Zoysia matrella [L.] Merr. not only broaden the theoretical information of salt tolerance, but also provide new salt-resistant genetic resources for crop breeding. The salt-inducible protein disulfide isomerase (ZmPDI) of Zoysia matrella [L.] Merr. was proved to enhance salt tolerance in homologous overexpression transgenic plants. In order to evaluate its potential application in crops, we conducted the salt tolerance evaluation in heterologous overexpression transgenic rice (OX-ZmPDI), Wild-type (WT) rice, and LOC_Os11g09280 (OsPDI, homologous gene of ZmPDI in rice) knock-out rice generated by CRISPR-Cas9 system (CR-OsPDI). Our findings revealed that OX-ZmPDI rice was higher and exhibited longer main root length, more proline (Pro) and malondialdehyde (MDA), and higher peroxidase (POD) activity than WT control after salt treatment, while CR-OsPDI resulted in contrary phenotypes. These results indicated that ZmPDI can significantly enhance the salt tolerance in rice, whereas loss-of-function of OsPDI reduces the salt tolerance. To further investigate these differences at the molecular level, we collected roots from OX-ZmPDI transgenic, CR-OsPDI transgenic, and wild-type (WT) plants at 0 and 24 h after salt treatment for RNA-seq and data-independent acquisition (DIA) proteome sequencing. Combined analysis of the transcriptome and proteome revealed that ZmPDI has the potential to enhance the salt tolerance of rice by modulating the expression of laccase-6, zingipain-2, WIP3, FKBP65, AKR4C10, GBSSII, Pho1, and TRXf1. Those results provided new information for the molecular regulation mechanism by which ZmPDI improves salt tolerance, and prove the potential of ZmPDI for application in crop breeding.

To solve the high error phenomenon of microelectromechanical systems (MEMS) due to their poor signal-to-noise ratio, this paper proposes an online compensation algorithm wavelet threshold back-propagation neural network (WT-BPNN), based on a neural network and designed to effectively suppress the random error of MEMS arrays. The algorithm denoises MEMS and compensates for the error using a back propagation neural network (BPNN). To verify the feasibility of the proposed algorithm, we deployed it in a ZYNQ-based MEMS array hardware. The experimental results showed that the zero-bias instability, angular random wander, and angular velocity random wander of the gyroscope were improved by about 12 dB, 10 dB, and 7 dB, respectively, compared with the original device in static scenarios, and the dispersion of the output data was reduced by about 8 dB in various dynamic environments, which effectively verified the robustness and feasibility of the algorithm.

Abstract Immune checkpoint inhibitor (ICI)‐based therapies have shown promising advances for the first‐line treatment of advanced or metastatic esophageal cancer (EC). However, few studies concerning the identification of patients who achieve durable response from ICIs have been previously reported. In the present study, pre‐ and on‐treatment plasma circulating tumor DNA (ctDNA) were analyzed in 10 patients with advanced esophageal squamous cell cancer (ESCC) receiving first‐line chemoimmunotherapy. Patients with decreased molecular tumor burden index (mTBI) >7% experienced longer progression‐free survival (PFS) and durable clinical benefit (DCB, PFS ≥ 6 months). In addition, five patients showed stable disease at first scan, all three patients with decreased mTBI > 7% achieved DCB, while two cases with decreased mTBI ≤ 7% experienced non‐DCB. Our results demonstrate that ctDNA monitor might help identify which ESCC patients respond to chemoimmunotherapy.

Abstract Background Precision medicine highlights the importance of incorporating molecular genetic testing into standard clinical care. Next-generation sequencing can detect cancer-specific gene mutations, and molecular-targeted drugs can be designed to be effective for one or more specific gene mutations. For patients with special site metastases, it is particularly important to use appropriate samples for genetic profiling. This study aimed to determine whether genomic profiling using ASC and PE is effective in detecting genetic mutations. Methods Tissues, plasma, ascites (ASC) supernatants, and pleural effusion (PE) samples from gastrointestinal cancer patients with peritoneal metastasis and lung cancer patients with pleural metastasis were collected for comprehensive genomic profiling. The samples were subjected to next-generation sequencing using a panel of 59 or 1021 cancer-relevant genes panel. Results A total of 156 tissues, 188 plasma samples, 45 ASC supernatants, and 1 PE samples from 304 gastrointestinal cancer patients and 446 PE supernatants, 122 tissues, 389 plasma samples, and 45 PE sediments from 407 lung cancer patients were analyzed. The MSAF was significantly higher in ASC and PE supernatant than that in plasma ctDNA (50.00% vs. 3.00%, p

BackgroundThe incidence of thyroid cancer in China has rapidly increased in recent decades. As the genetic profiles of thyroid cancer vary dramatically between different geographical regions, a comprehensive genetic landscape of thyroid cancer in the Chinese population is urgently needed.MethodsWe retrospectively included thyroid cancer patients from three Chinese medical centers between February 2015 and August 2020. To dissect the genomic profiling of these patients, we performed targeted next-generation sequencing on their tumor tissues using a 1,021-gene panel.ResultsA total of 458 Chinese patients with thyroid cancer were enrolled, including four malignant histological subtypes arising from follicular epithelial thyroid cells. BRAF driver mutations were identified in 76.0% of patients, followed by RET rearrangements (7.6%) and RAS driver mutations (4.1%). Tumors with more somatic mutations correlated with worse clinical characteristics, including older age at diagnosis, less differentiation of tumor, larger tumor size, lymph node metastasis and distal metastasis. Subclonal BRAF mutations occurred in 20% (6/30) of patients and were frequent in poorly differentiated or anaplastic tumors (33.3% [2/6] vs. 4.2% [1/24], P = 0.09) and those with distal metastasis (50.0% [2/4] vs. 8.7% [2/23], P = 0.09). Tumors with TERT promoter mutations had significantly more somatic mutations (average: 6.5 vs. 1.8, P < 0.001). Moreover, TERT promoter mutations were not associated with lymph node metastasis but significantly associated with older age at diagnosis and poorly differentiated or anaplastic tumors, regardless of their clonal architecture.ConclusionOur results shed light on the molecular pathogenesis and clinical characteristics of thyroid cancer in the Chinese population. The number of somatic mutations, TERT promoter mutations, and the clonal architecture of BRAF mutations should be considered in the risk stratification of thyroid cancer.

Abstract Background Neoadjuvant immunotherapy is emerging as novel effective intervention in lung cancer, but study to unearth effective surrogates indicating its therapeutic outcomes is limited. We investigated the genetic changes between non-small cell lung cancer (NSCLC) patients with varied response to neoadjuvant immunotherapy and discovered highly potential biomarkers with indicative capability in predicting outcomes. Methods In this study, 3 adenocarcinoma and 11 squamous cell carcinoma NSCLC patients were treated by neoadjuvant immunotherapy with variated regimens followed by surgical resection. Treatment-naive FFPE or fresh tissues and blood samples were subjected to whole-exome sequencing (WES). Genetic alternations were compared between differently-responded patients. Findings were further validated in multiple public cohorts. Results DNA damage repair (DDR)-related InDel signatures and DDR-related gene mutations were enriched in better-responded patients, i.e., major pathological response (MPR) group. Besides, MPR patients exhibited provoked genome instability and unique homologous recombination deficiency (HRD) events. By further inspecting alternation status of homology-dependent recombination (HR) pathway genes, the clonal alternations were exclusively enriched in MPR group. Additionally, associations between HR gene alternations, percentage of viable tumor cells and HRD event were identified, which orchestrated tumor mutational burden (TMB), mutational intratumor heterogeneity (ITH), somatic copy number alteration (SCNA) ITH and clonal neoantigen load in patients. Validations in public cohorts further supported the generality of our findings. Conclusions We reported for the first time the association between HRD event and enhanced neoadjuvant immunotherapy response in lung cancer. The power of HRD event in patient therapeutic stratification persisted in multifaceted public cohorts. We propose that HR pathway gene status could serve as novel and additional indicators guiding immune-neoadjuvant and immunotherapy treatment decisions for NSCLC patients.