Real-world effectiveness of adjuvant octreotide therapy in patients with pancreatic neuroendocrine tumors at high recurrence risk: A multicenter retrospective cohort study.

Adjuvant therapy for pancreatic neuroendocrine tumors (PanNETs) after radical resection lacks evidence-based data and remains controversial. This study aimed to validate whether long-acting octreotide is a potential candidate for adjuvant therapy in patients with G2 PanNETs at high recurrence risk by clustering real-world data. A retrospective review of patients with nonmetastatic grade 2 PanNETs who underwent radical resection at six research centers between 2008 and 2020 was conducted. Propensity score matching and inverse probability of treatment weight analysis were used to control confounding factors. Overall, 357 patients (octreotide group, n = 82; control group, n = 275) were analyzed. Kaplan-Meier survival analyses showed that the octreotide group had longer disease-free survival (DFS) compared with the control group (36 months: 93.3% vs. 79.0%, p = .0124; 60 months: 71% vs. 67.6%, p = .0596, respectively), as well as overall survival (OS) (60 months: 98% vs. 83.8%, p = .0117, respectively). Multivariate analyses indicated that octreotide long-acting repeatable (LAR) adjuvant therapy was associated with higher OS (p = .0270) at 60 months. Propensity score matching analysis showed that octreotide adjuvant therapy was associated with higher DFS (p = .0455) and OS (p = .0190) at 60 months. Similar results were obtained via inverse probability of treatment weight analysis. Subgroup analysis indicated that octreotide LAR was associated with a high DFS in patients with lymph node metastasis or Ki-67 <10% PanNETs. Adjuvant therapy with long-acting octreotide following radical resection of nonmetastatic G2 PanNETs may be associated with improved DFS and OS in a real-world setting.

Ammonium enhances rice resistance to Magnaporthe oryzae through H2O2 accumulation.

Nitrogen (N) is essential for the physiological processes of plants. However, the specific mechanisms by which different nitrogen forms influence rice blast pathogenesis remain poorly understood. This study used hydroponic assays to explore how ammonium (NH4+) and nitrate (NO3-) affect rice after inoculation with Magnaporthe oryzae (M. oryzae). The results showed that NH4+, compared to NO3-, significantly reduced disease severity, fungal growth, fungal hyphae number, the expansion capacity of infectious hyphae, and disease-related loss of photosynthesis. Additionally, NH4+ enhanced the expression of defense-related genes, including OsPBZ1, OsCHT1, OsPR1a, and OsPR10. NH4+-treated rice also exhibited higher hydrogen peroxide (H2O2) accumulation and increased antioxidant enzyme activities. Moreover, susceptibility to rice blast disease increased when H2O2 was scavenged, while a reduction in susceptibility was observed with the application of exogenous H2O2. These results suggest that ammonium enhances rice resistance to M. oryzae, potentially through H2O2 accumulation. The findings provide valuable insights into how different nitrogen forms affect plant immunity in rice, which is crucial for controlling rice blast and ensuring stable food production.

Exploring the Potential Mechanisms of Zhu-Ye-Qing Wine in Preventing Cardiovascular and Cerebrovascular Diseases Based on Network Pharmacology.

Cardiovascular and cerebrovascular disease (CCVD) is a complex disease with a long latency period, and the most effective diagnosis and treatment methods are risk assessment and preventive interventions before onset. According to traditional Chinese medicine (TCM), Zhu-Ye-Qing wine (ZYQW) has the effect of invigorating blood and removing blood stasis. However, whether ZYQW can improve the progression of CCVD has not been reported. This study aims to explore the possible mechanism of ZYQW on CCVD through network pharmacology, and finally 249 potential targets of ZYQW and 2080 potential targets of CCVD are obtained. The key targets mainly include MAPK3, TP53, RELA, MAPK1 and AKT1. The main KEGG pathways include TNF signaling pathway, lipid and atherosclerosis pathway signaling pathway. The components in ZYQW are identified by ultra-performance liquid chromatography-mass spectrometry (UHPLC-CQE-CQE-MS/MS). Through network pharmacology, molecular docking and molecular dynamics simulation, the potential key components and prevention mechanisms of ZYQW in the prevention of CCVD are determined. ZYQW may be an effective and safe health food for the prevention of CCVD, providing guidance and basis for the further development of medicinal foods.

A Miniature Modular Fluorescence Flow Cytometry System.

Fluorescence flow cytometry is a powerful instrument to distinguish cells or particles labelled with high-specificity fluorophores. However, traditional flow cytometry is complex, bulky, and inconvenient for users to adjust fluorescence channels. In this paper, we present a modular fluorescence flow cytometry (M-FCM) system in which fluorescence channels can be flexibly arranged. Modules for particle focusing and fluorescence detection were developed. After hydrodynamical focusing, the cells were measured in the detection modules, which were integrated with in situ illumination and fluorescence detection. The signal-to-noise ratio of the detection reached to 33.2 dB. The crosstalk among the fluorescence channels was eliminated. The M-FCM system was applied to evaluate cell viability in drug screening, agreeing well with the commercial cytometry. The modular cytometry presents several outstanding features: flexibility in setting fluorescence channels, cost efficiency, compact construction, ease of operation, and the potential to upgrade for multifunctional measurements. The modular cytometry provides a multifunctional platform for various biophysical measurements, e.g., electrical impedance and refractive-index detection. The proposed work paves an innovative avenue for the multivariate analysis of cellular characteristics.

Enhancing plant resilience: arbuscular mycorrhizal fungi's role in alleviating drought stress in vegetation concrete.

Introduction: Drought stress usually inhibits plant growth, which may increase the difficulty of greening slopes. Methods: In this study, we systematically investigated the effects of arbuscular mycorrhizal (AM) fungi on the growth and drought tolerance of two plant species, Festuca elata and Cassia glauca, in a vegetation concrete environment by exogenously inoculating AM fungi and setting three drought levels: well water, moderate drought and severe drought. The results showed that plant growth was significantly inhibited under drought stress; however, AM fungi inoculation significantly promoted plant height, root length, and above- and belowground biomass in these two plant species. Results: Compared with, those in the CK treatment, the greatest increases in the net photosynthesis rate, stomatal conductance and transpiration rate in the AM treatment group were 36.72%, 210.08%, and 66.41%, respectively. Moreover, inoculation with AM fungi increased plant superoxide dismutase and catalase activities by 4.70-150.73% and 9.10-95.70%, respectively, and reduced leaf malondialdehyde content by 2.79-55.01%, which alleviated the damage caused by oxidative stress. These effects alleviated the damage caused by oxidative stress and increased the content of soluble sugars and soluble proteins in plant leaves by 1.52-65.44% and 4.67-97.54%, respectively, which further increased the drought adaptability of plants. However, inoculation with AM fungi had different effects on different plants. Conclusion: In summary, this study demonstrated that the inoculation of AM fungi in vegetation concrete environments can significantly increase plant growth and drought tolerance. The plants that formed a symbiotic structure with AM fungi had a larger root uptake area, greater water uptake capacity, and greater photosynthesis and gas exchange efficiency. In addition, AM fungi inoculation further increased the drought adaptability of the plants by increasing their antioxidant enzyme activity and regulating their metabolite content. These findings are highly important for promoting plant growth and increasing drought tolerance under drought conditions, especially for potential practical applications in areas such as slope protection, and provide useful references for future ecological engineering and sustainable development.

Variation of mesophyll conductance mediated by nitrogen form is related to changes in cell wall property and chloroplast number.

Plants primarily incorporate nitrate (NO3 -) and ammonium (NH4 +) as the primary source of inorganic nitrogen (N); the physiological mechanisms of photosynthesis (A) dropdown under NH4 + nutrition has been investigated in many studies. Leaf anatomy is a major determinant to mesophyll conductance (g m) and photosynthesis; however, it remains unclear whether the photosynthesis variations of plants exposed to different N forms is related to leaf anatomical variation. In this work, a common shrub, Lonicera japonica was hydroponically grown under NH4 +, NO3 - and 50% NH4 +/NO3 -. We found that leaf N significantly accumulated under NH4 +, whereas the photosynthesis was significantly decreased, which was mainly caused by a reduced g m. The reduced g m under NH4 + was related to the decreased intercellular air space, the reduced chloroplast number and especially the thicker cell walls. Among the cell wall components, lignin and hemicellulose contents under NH4 + nutrition were significantly higher than those in the other two N forms and were scaled negatively correlated with g m; while pectin content was independent from N forms. Pathway analysis further revealed that the cell wall components might indirectly regulate g m by influencing the thickness of the cell wall. These results highlight the importance of leaf anatomical variation characterized by modifications of chloroplasts number and cell wall thickness and compositions, in the regulation of photosynthesis in response to varied N sources.

Integrated 68 Ga-FAPI-04 PET/MR in Pancreatic Cancer : Prediction of Tumor Response and Tumor Resectability After Neoadjuvant Therapy.

PURPOSE: This study aimed to investigate the value of 68 Ga-fibroblast activation protein inhibitor (FAPI) PET/MR semiquantitative parameters in the prediction of tumor response and resectability after neoadjuvant therapy in patients with pancreatic cancer. PATIENTS AND METHODS: This study was performed retrospectively in patients with borderline resectable or locally advanced pancreatic cancer who underwent 68 Ga-FAPI PET/MRI from June 2020 to June 2022. The SUV max , SUV mean , SUV peak , uptake tumor volume (UTV), and total lesion FAP expression (TLF) of the primary tumor were recorded. The target-to-background ratios (TBRs) of the primary tumor to normal tissue muscle (TBR muscle ) and blood (TBR blood ) were also calculated. In addition, the minimum apparent diffusion coefficient value of the tumor was measured. After 3-4 cycles of gemcitabine + nab-paclitaxel chemotherapy, patients were divided into responders and nonresponders groups according to RECIST criteria (v.1.1). They were also divided into resectable and unresectable groups according to the surgical outcome. The variables were compared separately between groups. RESULTS: A total of 18 patients who met the criteria were included in this study. The UTV and TLF were significantly higher in nonresponders than in responders ( P < 0.05). The SUV max , SUV mean , and TBR muscle were significantly higher in unresectable patients than in resectable ones ( P < 0.05). Receiver operating characteristic curve analysis identified UTV (area under the curve [AUC] = 0.840, P = 0.015) and TLF (AUC = 0.877, P = 0.007) as significant predictors for the response to gemcitabine + nab-paclitaxel chemotherapy, with cutoff values of 25.05 and 167.38, respectively. In addition, SUV max (AUC = 0.838, P = 0.016), SUV mean (AUC = 0.812, P = 0.026), and TBR muscle (AUC = 0.787, P = 0.041) were significant predictors of the resectability post-NCT, with cutoff values of 14.0, 6.0, and 13.9, respectively. According to logistic regression analysis, TLF was found to be significantly associated with tumor response ( P = 0.032) and was an independent predictor of tumor response ( P = 0.032). In addition, apparent diffusion coefficient value was an independent predictor of tumor resectability ( P = 0.043). CONCLUSIONS: This pilot study demonstrates the value of 68 Ga-FAPI PET/MR for the prediction of tumor response and resectability after neoadjuvant therapy. It may aid in individualized patient management by guiding the treatment regimens.

Early Diagnosis of Colorectal Cancer Based on Bisulfite-free Site-specific Methylation Identification PCR Strategy: High-Sensitivity, Accuracy, and Primary Medical Accessibility.

Due to its decade-long progression, colorectal cancer (CRC) is most suitable for population screening to achieve a significant reduction in its incidence and mortality. DNA methylation has emerged as a potential marker for the early detection of CRC. However, the current mainstream methylation detection method represented by bisulfite conversion has issues such as tedious operation, DNA damage, and unsatisfactory sensitivity. Herein, a new high-performance CRC screening tool based on the promising specific terminal-mediated polymerase chain reaction (STEM-PCR) strategy is developed. CRC-related methylation-specific candidate CpG sites are first prescreened through The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases using self-developed bioinformatics. Next, 9 homebrew colorectal cancer DNA methylated STEM‒PCR assays (ColoC-mSTEM) with high sensitivity (0.1%) and high specificity are established to identify candidate sites. The clinical diagnostic performance of these selected methylation sites is confirmed and validated by a case-control study. The optimized diagnostic model has an overall sensitivity of 94.8% and a specificity of 95.0% for detecting early-stage CRC. Taken together, ColoC-mSTEM, based on a single methylation-specific site, is a promising diagnostic approach for the early detection of CRC which is perfectly suitable for the screening needs of CRC in primary healthcare institutions.

Chromosome-level genome assembly of the threatened resource plant Cinnamomum chago.

Cinnamomum chago is a tree species endemic to Yunnan province, China, with potential economic value, phylogenetic importance, and conservation priority. We assembled the genome of C. chago using multiple sequencing technologies, resulting in a high-quality, chromosomal-level genome with annotation information. The assembled genome size is approximately 1.06 Gb, with a contig N50 length of 92.10 Mb. About 99.92% of the assembled sequences could be anchored to 12 pseudo-chromosomes, with only one gap, and 63.73% of the assembled genome consists of repeat sequences. In total, 30,497 genes were recognized according to annotation, including 28,681 protein-coding genes. This high-quality chromosome-level assembly and annotation of C. chago will assist us in the conservation and utilization of this valuable resource, while also providing crucial data for studying the evolutionary relationships within the Cinnamomum genus, offering opportunities for further research and exploration of its diverse applications.

Artemisia annua L. polysaccharide improves the growth performance and intestinal barrier function of broilers challenged with Escherichia coli.

With the high intensification of poultry breeding, a series of diseases caused by pathogenic bacteria threaten the health of poultry and human. Among them, poultry diseases induced by Escherichia coli cause significant economic loss every year. The aim of this study was to investigate the effects of dietary supplementation with Artemisia annua L. polysaccharide (AAP) on the growth performance and intestinal barrier function of broilers with Escherichia coli (E. coli) challenge. A total of 256 one-day-old chicks were randomly assigned to four treatment groups: control group (fed basal diet), AAP group (fed basal diet supplemented with AAP), E. coli group (fed basal diet and orally administered E. coli), AAP + E. coli group (fed basal diet supplemented with AAP and orally administered E. coli). Dietary AAP supplementation elevated the BW, ADG and ADFI in non-challenged broilers. AAP also increased the apparent metabolic rate of EE and Ca in E. coli-challenged broilers. Moreover, AAP not only enhanced the serum IgA content but also decreased the serum and jejunum content of IL-6, as well as the jejunum level of IL-1ß in non-challenged broilers. AAP also down-regulates the mRNA level of inflammatory factors (IL-1ß, IL-6, and TNF-α) by inhibiting the mRNA expression of TLR4 and MyD88 in intestinal NF-κB signaling pathway of E. coli-challenged broilers. Meanwhile, AAP up-regulates the activity and mRNA level CAT by down-regulating the mRNA level of Keap1 in intestinal Nrf2 signaling pathway of E. coli-challenged broilers, and decreased serum MDA concentration. AAP significantly elevated the mRNA level of CAT, SOD and Nrf2 in jejunal of non-challenged broilers. Interestingly, AAP can improve intestinal physical barrier by down-regulating serum ET content, increasing the jejunal villus height/crypt depth (VH/CD) and ZO-1 mRNA level in broilers challenged by E. coli. AAP also elevated the VH/CD and the mRNA level of Occludin, ZO-1, Mucin-2 in non-challenged broilers. Importantly, AAP reshaped the balance of jejunum microbiota in E. coli-challenged broilers by altering α diversity and community composition. In summary, AAP ameliorated the loss of growth performance in broilers challenged with E. coli, probably by regulating the intestinal permeability and mucosa morphology, immune function, antioxidant ability, and microbiota.

Detection and characterization of pancreatic and biliary tract cancers using cell-free DNA fragmentomics.

BACKGROUND: Plasma cell-free DNA (cfDNA) fragmentomics has demonstrated significant differentiation power between cancer patients and healthy individuals, but little is known in pancreatic and biliary tract cancers. The aim of this study is to characterize the cfDNA fragmentomics in biliopancreatic cancers and develop an accurate method for cancer detection. METHODS: One hundred forty-seven patients with biliopancreatic cancers and 71 non-cancer volunteers were enrolled, including 55 patients with cholangiocarcinoma, 30 with gallbladder cancer, and 62 with pancreatic cancer. Low-coverage whole-genome sequencing (median coverage: 2.9 ×) was performed on plasma cfDNA. Three cfDNA fragmentomic features, including fragment size, end motif and nucleosome footprint, were subjected to construct a stacked machine learning model for cancer detection. Integration of carbohydrate antigen 19-9 (CA19-9) was explored to improve model performance. RESULTS: The stacked model presented robust performance for cancer detection (area under curve (AUC) of 0.978 in the training cohort, and AUC of 0.941 in the validation cohort), and remained consistent even when using extremely low-coverage sequencing depth of 0.5 × (AUC: 0.905). Besides, our method could also help differentiate biliopancreatic cancer subtypes. By integrating the stacked model and CA19-9 to generate the final detection model, a high accuracy in distinguishing biliopancreatic cancers from non-cancer samples with an AUC of 0.995 was achieved. CONCLUSIONS: Our model demonstrated ultrasensitivity of plasma cfDNA fragementomics in detecting biliopancreatic cancers, fulfilling the unmet accuracy of widely-used serum biomarker CA19-9, and provided an affordable way for accurate noninvasive biliopancreatic cancer screening in clinical practice.

Carbon starvation raises capacities in bacterial antibiotic resistance and viral auxiliary carbon metabolism in soils.

Organic carbon availability in soil is crucial for shaping microbial communities, yet, uncertainties persist concerning microbial adaptations to carbon levels and the ensuing ecological and evolutionary consequences. We investigated organic carbon metabolism, antibiotic resistance, and virus-host interactions in soils subjected to 40 y of chemical and organic fertilization that led to contrasting carbon availability: carbon-poor and carbon-rich soils, respectively. Carbon-poor soils drove the enrichment of putative genes involved in organic matter decomposition and exhibited specialization in utilizing complex organic compounds, reflecting scramble competition. This specialization confers a competitive advantage of microbial communities in carbon-poor soils but reduces their buffering capacity in terms of organic carbon metabolisms, making them more vulnerable to environmental fluctuations. Additionally, in carbon-poor soils, viral auxiliary metabolic genes linked to organic carbon metabolism increased host competitiveness and environmental adaptability through a strategy akin to "piggyback the winner." Furthermore, putative antibiotic resistance genes, particularly in low-abundance drug categories, were enriched in carbon-poor soils as an evolutionary consequence of chemical warfare (i.e., interference competition). This raises concerns about the potential dissemination of antibiotic resistance from conventional agriculture that relies on chemical-only fertilization. Consequently, carbon starvation resulting from long-term chemical-only fertilization increases microbial adaptations to competition, underscoring the importance of implementing sustainable agricultural practices to mitigate the emergence and spread of antimicrobial resistance and to increase soil carbon storage.

Global analysis of T-cell groups reveals immunological features and common antigen targets of digestive tract tumors.

BACKGROUND: T cells are key players in the tumor immune microenvironment (TIME), as they can recognize and eliminate cancer cells that express neoantigens derived from somatic mutations. However, the diversity and specificity of T-cell receptors (TCRs) that recognize neoantigens are largely unknown, due to the high variability of TCR sequences among individuals. METHODS: To address this challenge, we applied GLIPH2, a novel algorithm that groups TCRs based on their predicted antigen specificity and HLA restriction, to cluster the TCR repertoire of 1,702 patients with digestive tract cancer. The patients were divided into five groups based on whether they carried tumor-infiltrating or clonal-expanded TCRs and calculated their TCR diversity. The prognosis, tumor subtype, gene mutation, gene expression, and immune microenvironment of these groups were compared. Viral specificity inference and immunotherapy relevance analysis performed for the TCR groups. RESULTS: This approach reduced the complexity of TCR sequences to 249 clonally expanded and 150 tumor-infiltrating TCR groups, which revealed distinct patterns of TRBV usage, HLA association, and TCR diversity. In gastric adenocarcinoma (STAD), patients with tumor-infiltrating TCRs (Patients-TI) had significantly worse prognosis than other patients (Patients-nonTI). Patients-TI had richer CD8+ T cells in the immune microenvironment, and their gene expression features were positively correlated with immunotherapy response. We also found that tumor-infiltrating TCR groups were associated with four distinct tumor subtypes, 26 common gene mutations, and 39 gene expression signatures. We discovered that tumor-infiltrating TCRs had cross-reactivity with viral antigens, indicating a possible link between viral infections and tumor immunity. CONCLUSION: By applying GLIPH2 to TCR sequences from digestive tract tumors, we uncovered novel insights into the tumor immune landscape and identified potential candidates for shared TCRs and neoantigens.

Assemblages of rhizospheric and root endospheric mycobiota and their ecological associations with functional traits of rice.

The soil-root interface harbors complex fungal communities that play vital roles in the fitness of host plants. However, little is known about the assembly rules and potential functions of rhizospheric and endospheric mycobiota. A greenhouse experiment was conducted to explore the fungal communities inhabiting the rhizosphere and roots of 87 rice cultivars at the tillering stage via amplicon sequencing of the fungal internal transcribed spacer 1 region. The potential relationships between these communities and host plant functional traits were also investigated using Procrustes analysis, generalized additive model fitting, and correlation analysis. The fungal microbiota exhibited greater richness, higher diversity, and lower structural variability in the rhizosphere than in the root endosphere. Compared with the root endosphere, the rhizosphere supported a larger coabundance network, with greater connectivity and stronger cohesion. Null model-based analyses revealed that dispersal limitation was primarily responsible for rhizosphere fungal community assembly, while ecological drift was the dominant process in the root endosphere. The community composition of fungi in the rhizosphere was shown to be more related to plant functional traits, such as the root/whole plant biomass, root:shoot biomass ratio, root/shoot nitrogen (N) content, and root/shoot/whole plant N accumulation, than to that in the root endosphere. Overall, at the early stage of rice growth, diverse and complex rhizospheric fungal communities are shaped by stochastic-based processes and exhibit stronger associations with plant functional traits. IMPORTANCE: The assembly processes and functions of root-associated mycobiota are among the most fascinating yet elusive topics in microbial ecology. Our results revealed that stochastic forces (dispersal limitation or ecological drift) act on fungal community assembly in both the rice rhizosphere and root endosphere at the early stage of plant growth. In addition, high covariations between the rhizosphere fungal community compositions and plant functional trait profiles were clearly demonstrated in the present study. This work provides empirical evidence of the root-associated fungal assembly principles and ecological relationships of plant functional traits with rhizospheric and root endospheric mycobiota, thereby potentially providing novel perspectives for enhancing plant performance.

Active microbial population dynamics and life strategies drive the enhanced carbon use efficiency in high-organic matter soils.

Microbial carbon use efficiency (CUE) is a critical parameter that controls carbon storage in soil, but many uncertainties remain concerning adaptations of microbial communities to long-term fertilization that impact CUE. Based on H218O quantitative stable isotope probing coupled with metagenomic sequencing, we disentangled the roles of active microbial population dynamics and life strategies for CUE in soils after a long-term (35 years) mineral or organic fertilization. We found that the soils rich in organic matter supported high microbial CUE, indicating a more efficient microbial biomass formation and a greater carbon sequestration potential. Organic fertilizers supported active microbial communities characterized by high diversity and a relative increase in net growth rate, as well as an anabolic-biased carbon cycling, which likely explains the observed enhanced CUE. Overall, these results highlight the role of population dynamics and life strategies in understanding and predicting microbial CUE and sequestration in soil.IMPORTANCEMicrobial CUE is a major determinant of global soil organic carbon storage. Understanding the microbial processes underlying CUE can help to maintain soil sustainable productivity and mitigate climate change. Our findings indicated that active microbial communities, adapted to long-term organic fertilization, exhibited a relative increase in net growth rate and a preference for anabolic carbon cycling when compared to those subjected to chemical fertilization. These shifts in population dynamics and life strategies led the active microbes to allocate more carbon to biomass production rather than cellular respiration. Consequently, the more fertile soils may harbor a greater microbially mediated carbon sequestration potential. This finding is of great importance for manipulating microorganisms to increase soil C sequestration.

Prospective observational study on biomarkers of response in pancreatic ductal adenocarcinoma.

Adjuvant chemotherapy benefits patients with resected pancreatic ductal adenocarcinoma (PDAC), but the compromised physical state of post-operative patients can hinder compliance. Biomarkers that identify candidates for prompt adjuvant therapy are needed. In this prospective observational study, 1,171 patients with PDAC who underwent pancreatectomy were enrolled and extensively followed-up. Proteomic profiling of 191 patient samples unveiled clinically relevant functional protein modules. A proteomics-level prognostic risk model was established for PDAC, with its utility further validated using a publicly available external cohort. More importantly, through an interaction effect regression analysis leveraging both clinical and proteomic datasets, we discovered two biomarkers (NDUFB8 and CEMIP2), indicative of the overall sensitivity of patients with PDAC to adjuvant chemotherapy. The biomarkers were validated through immunohistochemistry on an internal cohort of 386 patients. Rigorous validation extended to two external multicentic cohorts-a French multicentric cohort (230 patients) and a cohort from two grade-A tertiary hospitals in China (466 patients)-enhancing the robustness and generalizability of our findings. Moreover, experimental validation through functional assays was conducted on PDAC cell lines and patient-derived organoids. In summary, our cohort-scale integration of clinical and proteomic data demonstrates the potential of proteomics-guided prognosis and biomarker-aided adjuvant chemotherapy for PDAC.

Hand-sewn gastrojejunal anastomosis reduces delayed gastric emptying after pancreaticoduodenectomy: A single-center retrospective clinical study of 1,077 consecutive patients.

BACKGROUND: Hand-sewn anastomosis and stapled anastomosis are the 2 main types of gastrojejunal anastomotic methods in pancreaticoduodenectomy. There is ongoing debate regarding the most effective anastomotic method for reducing delayed gastric emptying after pancreaticoduodenectomy. This study aims to identify factors that influence delayed gastric emptying after pancreaticoduodenectomy and assess the impact of different anastomotic methods on delayed gastric emptying. METHODS: The study included 1,077 patients who had undergone either hand-sewn anastomosis (n = 734) or stapled anastomosis (n = 343) during pancreaticoduodenectomy between December 2016 and November 2021 at our department. We retrospectively analyzed the clinical data, and a 1:1 propensity score matching was performed to balance confounding variables. RESULTS: After propensity score matching, 320 patients were included in each group. Compared with the stapled anastomosis group, the hand-sewn anastomosis group had a significantly lower incidence of delayed gastric emptying (28 [8.8%] vs 55 [17.2%], P = .001) and upper gastrointestinal tract bleeding (6 [1.9%] vs 17 [5.3%], P = .02). Additionally, the hand-sewn anastomosis group had a significantly reduced postoperative length of stay and lower hospitalization expenses. However, the hand-sewn anastomosis group had a significantly longer operative time, which was consistent with the analysis before propensity score matching. Logistic regression analysis showed that stapled anastomosis, intra-abdominal infection, and clinically relevant postoperative pancreatic fistula were independent prognostic factors for delayed gastric emptying. CONCLUSION: Hand-sewn anastomosis was associated with a lower incidence rate of clinically relevant delayed gastric emptying after pancreaticoduodenectomy. Stapled anastomosis, intra-abdominal infection, and clinically relevant postoperative pancreatic fistula could increase the incidence of postoperative clinically relevant delayed gastric emptying. Hand-sewn anastomosis should be considered by surgeons to reduce the occurrence of postoperative delayed gastric emptying and improve patient outcomes.

Early oral feeding versus nasojejunal early enteral nutrition in patients following pancreaticoduodenectomy: a propensity score-weighted analysis of 428 consecutive patients.

BACKGROUND: Notwithstanding that significant medical progress has been achieved in recent years, the optimal nutritional support method following pancreaticoduodenectomy (PD) remains uncertain. This study compared the safety and feasibility of early oral feeding (EOF) with nasojejunal early enteral nutrition (NJEEN) after PD. METHODS: A retrospective cohort study was conducted on 428 consecutive patients who underwent PD between August 2018 and December 2020. During the first study phase, the routine postoperative feeding strategy was NJEEN, later replaced by EOF during the second study phase. The primary outcome was the incidence of delayed gastric emptying (DGE) following PD. Propensity score weighting was used to control for confounding factors. RESULTS: Four hundred forty patients underwent PD during the overall study period, with 438 patients aged 18 years and older. Ten patients experienced accidental tube dislodgement or migration and were excluded from the study based on the exclusion criteria. Finally, 211 patients and 217 patients underwent EOF and NJEEN, respectively. After propensity score weighting, it was observed that patients who underwent postoperative EOF experienced a significantly lower DGE (B/C) rate compared to those who underwent postoperative NJEEN [7.38% (31/424) vs. 14.97% (62/413), P =0.0005]. Subgroup analyses according to the presence of soft pancreatic texture yielded consistent results. The EOF group exhibited lower DGE grade, DGE (B/C) rate [5.90% (11/194) vs. 22.07% (43/193), P <0.0001], postoperative gastrointestinal endoscopic intervention rate, and Clavien-Dindo Grade III or higher rate. CONCLUSIONS: EOF is superior to NJEEN in reducing the incidence of grade B/C DGE after PD. The EOF procedure is safe and feasible and should be recommended as the optimal postoperative feeding method following PD.

Functional characteristics of DNA N6-methyladenine modification based on long-read sequencing in pancreatic cancer.

Abnormalities of DNA modifications are closely related to the pathogenesis and prognosis of pancreatic cancer. The development of third-generation sequencing technology has brought opportunities for the study of new epigenetic modification in cancer. Here, we screened the N6-methyladenine (6mA) and 5-methylcytosine (5mC) modification in pancreatic cancer based on Oxford Nanopore Technologies sequencing. The 6mA levels were lower compared with 5mC and upregulated in pancreatic cancer. We developed a novel method to define differentially methylated deficient region (DMDR), which overlapped 1319 protein-coding genes in pancreatic cancer. Genes screened by DMDRs were more significantly enriched in the cancer genes compared with the traditional differential methylation method (P < 0.001 versus P = 0.21, hypergeometric test). We then identified a survival-related signature based on DMDRs (DMDRSig) that stratified patients into high- and low-risk groups. Functional enrichment analysis indicated that 891 genes were closely related to alternative splicing. Multi-omics data from the cancer genome atlas showed that these genes were frequently altered in cancer samples. Survival analysis indicated that seven genes with high expression (ADAM9, ADAM10, EPS8, FAM83A, FAM111B, LAMA3 and TES) were significantly associated with poor prognosis. In addition, the distinction for pancreatic cancer subtypes was determined using 46 subtype-specific genes and unsupervised clustering. Overall, our study is the first to explore the molecular characteristics of 6mA modifications in pancreatic cancer, indicating that 6mA has the potential to be a target for future clinical treatment.

Injectable alginate hydrogel promotes antitumor immunity through glucose oxidase and Fe3+ amplified RSL3-induced ferroptosis.

Ferroptosis induced by RAS-selective lethal small molecule 3 (RSL3) can trigger anti-tumor immune responses by reversing the immunosuppressive tumor microenvironment (TME). However, it is challenging to achieve sufficient ferroptosis in the tumor via RSL3 alone. Because of the excellent reactive oxygen species (ROS) production capacity of glucose oxidase (GOx) and Fe3+, we hypothesized that GOx and Fe3+ could increase intracellular lipid peroxidation (LPO) accumulation, and strengthen RSL3-induced ferroptosis in tumor cells. Herein we designed an in-situ gelation strategy based on sodium alginate (SA) to realize localized transport and specific retention of GOx, RSL3, and Fe3+ in tumor tissues. We loaded hydrophobic RSL3 with the tannic acid (TA)/Fe3+ complexes to form nanoparticles (RTF NPs). GOx diluted in the SA solution was blended with RTF NPs to obtain a homogeneous solution. The solution could form hydrogels in the tumor site (RTFG@SA) upon injection. The retained GOx and Fe3+ amplified the induction of ferroptosis by RSL3, augmented immunogenic cell death (ICD) and promoted antitumor immunity. The RTFG@SA hydrogel presented a significant restraint of tumor growth and metastasis in the 4T1 tumor model. This hydrogel could offer an effective means of co-delivery of hydrophilic drugs, hydrophobic drugs, and metal ions.