Quantitative Proteomics of Tissue-Infiltrating T Cells From CRC Patients Identified Lipocalin-2 Induces T-Cell Apoptosis and Promotes Tumor Cell Proliferation by Iron Efflux.

T cells play the most pivotal roles in antitumor immunity; the T-cell proteome and the differentially expressed proteins in the tumor immune microenvironment have rarely been identified directly from the clinical samples, especially for tumors that lack effective immunotherapy targets, such as colorectal cancer (CRC). In this study, we analyzed the protein expression pattern of the infiltrating T cells isolated from CRC patients using quantitative proteomics. CD4+ and CD8+ T cells were isolated from clinical samples and labeled by tandem mass tag reagents, and the differentially expressed proteins were quantified by mass spectrometry. The T-cell proteome profiling revealed dysfunctions in these tumor-infiltrating T cells. Specifically, antitumor immunity was suppressed because of differentially expressed metal ion transporters and immunity regulators. For the first time, lipocalin-2 (LCN2) was shown to be significantly upregulated in CD4+ T cells. Quantitative proteomic analysis of LCN2-overexpressed Jurkat cells showed that LCN2 damaged T cells by changes in iron transport. LCN2 induced T-cell apoptosis by reducing cellular iron concentration; moreover, the iron that was transported to the tumor microenvironment aided tumor cell proliferation, promoting tumor development. Meanwhile, LCN2 also influenced tumor progression through immune cytokines and cholesterol metabolism. Our results demonstrated that LCN2 has immunosuppressive functions that can promote tumor development; therefore, it is a potential immunotherapy target for CRC.

Quantitative Proteomic Analysis Reveals Functional Alterations of the Peripheral Immune System in Colorectal Cancer.

Colorectal cancer (CRC) is characterized by high morbidity, high mortality, and limited response to immunotherapies. The peripheral immune system is an important component of tumor immunity, and enhancements of peripheral immunity help to suppress tumor progression. However, the functional alterations of the peripheral immune system in CRC are unclear. Here, we used mass spectrometry-based quantitative proteomics to establish a protein expression atlas for the peripheral immune system in CRC, including plasma and five types of immune cells (CD4+ T cells, CD8+ T cells, monocytes, natural killer cells, and B cells). Synthesizing the results of the multidimensional analysis, we observed an enhanced inflammatory phenotype in CRC, including elevated expression of plasma inflammatory proteins, activation of the inflammatory pathway in monocytes, and increased inflammation-related ligand-receptor interactions. Notably, we observed tumor effects on peripheral T cells, including altered cell subpopulation ratios and suppression of cell function. Suppression of CD4+ T cell function is mainly mediated by high expression levels of protein tyrosine phosphatases. Among them, the expression of protein tyrosine phosphatase receptor type J (PTPRJ) gradually increased with CRC progression; knockdown of PTPRJ in vitro could promote T cell activation, thereby enhancing peripheral immunity. We also found that the combination of leucine-rich α-2 glycoprotein 1 (LRG1) and apolipoprotein A4 (APOA4) had the best predictive ability for colorectal cancer and has the potential to be a biomarker. Overall, this study provides a comprehensive understanding of the peripheral immune system in CRC. It also offers insights regarding the potential clinical utilities of these peripheral immune characteristics as diagnostic indicators and therapeutic targets.

Gastric Cancer Immune Subtypes and Prognostic Modeling: Insights from Aging-Related Gene Analysis.

Gastric cancer (GC) is highly heterogeneous and influenced by aging-related factors. This study aimed to improve individualized prognostic assessment of GC by identifying aging-related genes and subtypes. Immune scores of GC samples from GEO and TCGA databases were calculated using ESTIMATE and scored as high immune (IS_high) and low immune (IS_low). ssGSEA was used to analyze immune cell infiltration. Univariate Cox regression was employed to identify prognosis-related genes. LASSO regression analysis was used to construct a prognostic model. GSVA enrichment analysis was applied to determine pathways. CCK-8, wound healing, and Transwell assays tested the proliferation, migration, and invasion of the GC cell line (AGS). Cell cycle and aging were examined using flow cytometry, ß-galactosidase staining, and Western blotting. Two aging-related GC subtypes were identified. Subtype 2 was characterized as lower survival probability and higher risk, along with a more immune-responsive tumor microenvironment. Three genes (IGFBP5, BCL11B, and AKR1B1) screened from aging-related genes were used to establish a prognosis model. The AUC values of the model were greater than 0.669, exhibiting strong prognostic value. In vitro, IGFBP5 overexpression in AGS cells was found to decrease viability, migration, and invasion, alter the cell cycle, and increase aging biomarkers (SA-ß-galactosidase, p53, and p21). This analysis uncovered the immune characteristics of two subtypes and aging-related prognosis genes in GC. The prognostic model established for three aging-related genes (IGFBP5, BCL11B, and AKR1B1) demonstrated good prognosis performance, providing a foundation for personalized treatment strategies aimed at GC.

Selective and Scalable CO2 Electrolysis Enabled by Conductive Zinc Ion-Implanted Zeolite-Supported Cadmium Oxide Nanoclusters.

Catalyst supports play an essential role in catalytic reactions, hinting at pronounced metal-support effects. Zeolites are a propitious support in heterogeneous catalysts, while their use in the electrocatalytic CO2 reduction reaction has been limited as yet because of their electrically insulating nature and serious competing hydrogen evolution reaction (HER). Enlightened by theoretical prediction, herein, we implant zinc ions into the structural skeleton of a zeolite Y to strategically tailor a favorable electrocatalytic platform with remarkably enhanced electronic conduction and strong HER inhibition capability, which incorporates ultrafine cadmium oxide nanoclusters as guest species into the supercages of the tailored 12-ring window framework. The metal d-bandwidth tuning of cadmium by skeletal zinc steers the extent of substrate-molecule orbital mixing, enhancing the stabilization of the key intermediate *COOH while weakening the CO poisoning effect. Furthermore, the strong cadmium-zinc interplay causes a considerable thermodynamic barrier for water dissociation in the conversion of H+ to *H, potently suppressing the competing HER. Therefore, we achieve an industrial-level partial current density of 335 mA cm-2 and remarkable Faradaic efficiency of 97.1% for CO production and stably maintain Faradaic efficiency above 90% at the industrially relevant current density for over 120 h. This work provides a proof of concept of tailored conductive zeolite as a favorable electrocatalytic support for industrial-level CO2 electrolysis and will significantly enhance the adaptability of conductive zeolite-based electrocatalysts in a variety of electrocatalysis and energy conversion applications.

Multi-Target Joint Detection; Tracking and Classification Based on Marginal GLMB Filter and Belief Function Theory.

This paper proposes a new solution to multi-target joint detection, tracking and classification based on labeled random finite set (RFS) and belief function theory. A class dependent multi-model marginal generalized labeled multi-Bernoulli (MGLMB) filter is developed to analytically calculate the multi-target number, state estimates and model probabilities. In addition, a two-level classifier based on continuous transferable belief model (cTBM) is designed for target classification. To make full use of the kinematic characteristics for classification, both the dynamic modes and states are considered in the classifier, the model dependent class beliefs are computed on the continuous state feature subspace corresponding to different dynamic modes and then fused. As a result that the uncertainty about the classes is well described for decision, the classification results are more reasonable and robust. Moreover, as the estimation and classification problems are jointly solved, the tracking and classification performance are both improved. In the simulation, a scenario contains multi-target with miss detection and dense clutter is used. The performance of multi-target detection, tracking and classification is better than traditional methods based on Bayesian classifier or single model. Simulation results are illustrated to demonstrate the effectiveness and superiority of the proposed algorithm.

Control of Sleep Onset by Shal/Kv4 Channels in Drosophila Circadian Neurons.

Sleep is highly conserved across animal species. Both wake- and sleep-promoting neurons are implicated in the regulation of wake-sleep transition at dusk in Drosophila However, little is known about how they cooperate and whether they act via different mechanisms. Here, we demonstrated that in female Drosophila, sleep onset was specifically delayed by blocking the Shaker cognate L channels [Shal; also known as voltage-gated K+ channel 4 (Kv4)] in wake-promoting cells, including large ventral lateral neurons (l-LNvs) and pars intercerebralis (PI), but not in sleep-promoting dorsal neurons (DN1s). Delayed sleep onset was also observed in males by blocking Kv4 activity in wake-promoting neurons. Electrophysiological recordings show that Kv4 channels contribute A-type currents in LNvs and PI cells, but are much less conspicuous in DN1s. Interestingly, blocking Kv4 in wake-promoting neurons preferentially increased firing rates at dusk ∼ZT13, when the resting membrane potentials and firing rates were at lower levels. Furthermore, pigment-dispersing factor (PDF) is essential for the regulation of sleep onset by Kv4 in l-LNvs, and downregulation of PDF receptor (PDFR) in PI neurons advanced sleep onset, indicating Kv4 controls sleep onset via regulating PDF/PDFR signaling in wake-promoting neurons. We propose that Kv4 acts as a sleep onset controller by suppressing membrane excitability in a clock-dependent manner to balance the wake-sleep transition at dusk. Our results have important implications for the understanding and treatment of sleep disorders such as insomnia.SIGNIFICANCE STATEMENT The mechanisms by which our brains reversibly switch from waking to sleep state remain an unanswered and intriguing question in biological research. In this study, we identified that Shal/Kv4, a well known voltage-gated K+ channel, acts as a controller of wake-sleep transition at dusk in Drosophila circadian neurons. We find that interference of Kv4 function with a dominant-negative form (DNKv4) in subsets of circadian neurons specifically disrupts sleep onset at dusk, although Kv4 itself does not exhibit circadian oscillation. Kv4 preferentially downregulates neuronal firings at ZT9-ZT17, supporting that it plays an essential role in wake-sleep transition at dusk. Our findings may help understand and eventually treat sleep disorders such as insomnia.

The expression of microRNA-375 in plasma and tissue is matched in human colorectal cancer.

BACKGROUND: MicroRNAs (miRNAs) offer great potential as cancer biomarkers. The importance of miRNAs profiling in tissue and body fluids in colorectal cancer (CRC) have been addressed respectively in many studies. The purpose of our study is to systematically assess the expression of miRNAs in cancer tissue and matched plasma samples and to evaluate their usefulness as minimally invasive diagnostic biomarkers for the detection of CRC. METHODS: The study was divided into two phases: firstly, qRT-PCR based TaqMan Low Density MiRNA Arrays (TLDAs) was used to screen the differentially expressed miRNAs in 6 plasma samples of CRC patients and 6 healthy controls. Secondly, marker validation by stem-loop reverse transcription real-time PCR using an independent set of paired cancer tissues (n=88) and matched plasma samples (CRC, n=88; control, n=40). Correlation analysis was determined by Pearson's test. Receiver operating characteristic curve analyses were applied to obtain diagnostic utility of the differentially expressed miRNAs. Target gene prediction and signal pathway analyses were used to predict the function of miRNAs. RESULTS: TLDAs identified 42 miRNAs, which were differentially expressed in patients and healthy individuals. Five of them (miR-375, miR-150, miR-206, miR-125b and miR-126*) were chosen to be validated in plasma and tissue samples. The results indicated that for plasma sample, miR-375 (p<0.0001) and miR-206 (p=0.0002) were dysregulated and could discriminate CRC patients from healthy controls. For tissue samples, miR-375 (p<0.0001), miR-150 (p<0.0001), miR-125b (p=0.0065) and miR-126*(p=0.0009) were down-regulated. miR-375 was significantly down-regulated and positively correlated in both tissue and plasma samples (r=0.4663, p=0.0007). Gene ontology and signal pathway analyses showed that most of the target genes that were regulated by miR-375 were involved in some critical pathways in the development and progression of cancer. CONCLUSIONS: Our results indicate that the down-regulation of miR-375 in plasma and tissue is matched in CRC. Moreover, bioinformatics prediction revealed miR-375 association with some critical signal pathways in the development and progression of CRC. Therefore, plasma miR-375 holds great promise to be an alternative tissue biomarker for CRC detection.

Laparoscopy-assisted posterior low anterior resection of rectal cancer.

BACKGROUND: Laparoscopy-assisted low anterior resection (LAR) of colorectal cancer, using a posterior surgical approach, is a difficult and controversial procedure to perform. We report successful operations on 13 patients with clear surgical margins and no serious complications. METHODS: Thirteen patients [10 males and three females, age range: 48 to 69 years (median: 61 years)] with low adenocarcinoma confirmed by preoperative colonoscopic biopsy (four stage T1; nine stage T2) were resected. The distance from inferior edge of tumor to dentate line was 2 ~ 5 cm (average: 3.4 cm). Intraperitoneal laparoscopy was performed to isolate rectosigmoid and mesocolon moving toward distal end of the tumor. Perineal operation was performed in the prone clasp-knife position. RESULTS: The circumferential resection margin (CRM) was negative in all cases. No serious postoperative complications occurred. There were four cases of perineal wound infection, two cases with superficial perineal wound dehiscence, and two cases with persistent postoperative sacral pain. All 13 patients passed the Wexner continence test and had satisfactory anal function during a mean 18-month postoperative follow-up period. CONCLUSION: Laparoscopic posterior LAR of colorectal cancer is a safe and reliable treatment for patients with low colorectal cancer, increasing the chance of anal functional recovery. TRIAL REGISTRATION: Chinese Clinical Trial Register ChiCTR-ONC-14005145. Registered 19 August 2014.

[A prospective multicenter clinical trial of extralevator abdominoperineal excision for locally advanced low rectal cancer].

OBJECTIVE: To demonstrate the feasibility of extralevator abdominoperineal excision (ELAPE) for locally advanced low cancer in China. METHODS: A prospective multicenter clinical trial was carried out by 7 general hospitals across China from August 2008 to October 2011. A total of 102 patients underwent ELAPE for primary locally advanced low rectal cancer. There were 60 male and 42 female patients. The patients' characteristics, complications and prognosis were recorded. RESULTS: All patients underwent the ELAPE procedure successfully. The median operating time was 180 minutes (range 110-495 minutes) and median intraoperative blood loss was 200 ml (range 50-1000 ml). The rates of sexual dysfunction, perineal complications, urinary retention, and chronic perineal pain were 40.5%, 23.5%, 18.6% and 13.7%, respectively. Chronic perineal pain was associated with coccygectomy (12 months postoperatively, t = 8.06, P < 0.01), and the pain might gradually ease over time. Reconstruction of pelvic floor with biologic mesh was associated with lower rate of perineal dehiscence (χ(2) = 13.502, P = 0.006) and overall perineal wound complications (χ(2) = 5.836, P = 0.016) compared with primary closure. A positive circumferential margin (CRM) was demonstrated in 6 (5.9%) patients, and intraoperative perforations occurred in 4 (3.9%) patients. All CRM involvement and intraoperative perforation located at anteriorly and anterolaterally. The local recurrence was 4.9% at a median follow-up of 35 months (range, 18-58 months). CONCLUSIONS: ELAPE performed in the prone position for low rectal cancer leads to a reduction in CRM involvement, intraoperative perforations, and local recurrence, but it might result in a little high rate of perineal wound related complications. Reconstruction of pelvic floor with biologic mesh might lower the rate of perineal wound complications.

Identification and prognostic biomarkers among ZDHHC4/12/18/24, and APT2 in lung adenocarcinoma.

S-palmitoylases and S-depalmitoylases are differentially expressed in various cancers and several malignant tumors and show a strong prognostic ability. Notwithstanding, the potential clinical impact of S-palmitoylases and S-depalmitoylases, particularly in the prognosis and progression of lung adenocarcinoma (LUAD), has not been clarified. Expression levels of S-palmitoylases and S-depalmitoylases in LUAD were investigated using TCGA. GEPIA was used to evaluate the mRNA levels of S-palmitoylases and S-depalmitoylases at different pathological stages. Metascape was used to investigate the biological significance of S-palmitoylases and S-depalmitoylases. The Kaplan-Meier plotter was used to analyze the prognostic value of S-palmitoylases and S-depalmitoylases. CBioportal was used to analyze gene alterations in S-palmitoylases and S-depalmitoylases. UALCAN was used to examine DNA promoter methylation levels of S-palmitoylases and S-depalmitoylases. Finally, we investigated the relationship between S-palmitoylases, S-depalmitoylases, and tumor-infiltrating immune cells using TIMER. Correlations with immune checkpoint-related genes were determined using the R packages reshape2, ggpubr, ggplot2, and corrplot. PCR was also performed to assess the degree of ZDHHC4/12/18/24 and APT2 transcript expression in lung adenocarcinoma and adjacent normal lung tissues. HPA was utilized to investigate protein levels of S-palmitoylases and S-depalmitoylases in LUAD and normal lung tissue. Our study found that ZDHHC2/3/4/5/6/7/9/12/13/16/18/20/21/23/24, APT1/2, PPT1, LYPLAL1, ABHD4/10/11/12/13 and ABHD17C mRNA expression was significantly upregulated in LUAD, whereas ZDHHC1/8/11/11B/14/15/17/19/22, ABHD6/16A and ABHD17A mRNA expression was significantly downregulated. The functions of the differentially expressed S-palmitoylases and S-depalmitoylases were mainly associated with protein-cysteine S-palmitoyltransferase and protein-cysteine S-acyltransferase activities. Patients with high expression of ZDHHC4/12/18/24, APT2, ABHD4, ABHD11 and ABHD12 had a shorter overall survival. Infiltration of six immune cells (B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells) was closely associated with the expression of ZDHHC4/12/18/24 and APT2. ZDHHC4/12/18/24 and APT2 positively correlated with the immune checkpoint-related gene CD276. We assessed the mRNA levels of ZDHHC4/12/18/24 and APT2 using qRT-PCR and found increased expression of ZDHHC4/12/18/24 in LUAD compared with healty control lung tissues. ZDHHC4/12/18/24, and APT2 are potential prognostic biomarkers of LUAD. Their expression levels could be related to the tumor microenvironment in LUAD.

Conductive Zeolite Supported Indium-Tin Alloy Nanoclusters for Selective and Scalable Formic Acid Electrosynthesis.

Upgrading excess CO2 toward the electrosynthesis of formic acid is of significant research and commercial interest. However, simultaneously achieving high selectivity and industrially relevant current densities of CO2-to-formate conversion remains a grand challenge for practical implementations. Here, an electrically conductive zeolite support is strategically designed by implanting Sn ions into the skeleton structure of a zeolite Y, which impregnates ultrasmall In0.2Sn0.8 alloy nanoclusters into the supercages of the tailored 12-ring framework. The prominent electronic and geometric interactions between In0.2Sn0.8 nanoalloy and zeolite support lead to the delocalization of electron density that enhances orbital hybridizations between In active site and *OCHO intermediate. Thus, the energy barrier for the rate-limiting *OCHO formation step is reduced, facilitating the electrocatalytic hydrogenation of CO2 to formic acid. Accordingly, the developed zeolite electrocatalyst achieves an industrial-level partial current density of 322 mA cm-2 and remarkable Faradaic efficiency of 98.2% for formate production and stably maintains Faradaic efficiency above 93% at an industrially relevant current density for over 102 h. This work opens up new opportunities of conductive zeolite-based electrocatalysts for industrial-level formic acid electrosynthesis from CO2 electrolysis and toward practically accessible electrocatalysis and energy conversion.

Epidemiological investigation of lower respiratory tract infections during influenza A (H1N1) pdm09 virus pandemic based on targeted next-generation sequencing.

Background: Co-infection has been a significant contributor to morbidity and mortality in previous influenza pandemics. However, the current influenza A (H1N1) pdm09 virus pandemic, as the first major outbreak following the SARS-CoV-2 pandemic, may differ epidemiologically. Further investigation is necessary to understand the specific features and impact of this influenza A pandemic. Study design: We conducted a retrospective cohort study at a Chinese hospital between January and April 2023, focusing on patients with lower respiratory tract infections. Pathogen detection employed targeted next-generation sequencing (tNGS) on bronchoalveolar lavage fluid (BALF) or sputum samples. Results: This study enrolled 167 patients with lower respiratory tract infections, and the overall positivity rate detected through tNGS was around 80%. Among them, 40 patients had influenza A (H1N1) pdm09 virus infection, peaking in March. In these patients, 27.5% had sole infections, and 72.5% had co-infections, commonly with bacteria. The frequently detected pathogens were Aspergillus fumigatus, SARS-CoV-2, and Streptococcus pneumoniae. For non-influenza A virus-infected patients, the co-infection rate was 36.1%, with 42.3% having SARS-CoV-2. Patients with influenza A virus infection were younger, had more females and diabetes cases. Among them, those with sole infections were older, with less fever and asthma but more smoking history. Regarding prognosis, compared to sole influenza A virus infection, co-infected patients demonstrated higher 21-day recovery rates and a higher incidence of heart failure. However, they exhibited lower proportions of respiratory failure, acute kidney failure, septic shock, and hospital stays lasting more than 10 days. Interestingly, patients with non-influenza A virus infection had a significantly lower 21-day recovery rate. Correlation analysis indicated that the 21-day recovery rate was only associated with influenza A (H1N1) pdm09 virus. Conclusion: During the current pandemic, the influenza A (H1N1) pdm09 virus may have been influenced by the SARS-CoV-2 pandemic and did not exhibit a strong pathogenicity. In fact, patients infected with influenza A virus showed better prognoses compared to those infected with other pathogens. Additionally, tNGS demonstrated excellent detection performance in this study and showed great potential, prompting clinical physicians to consider its use as an auxiliary diagnostic tool.

Metabolomics analysis of MnO2 nanosheets CDT for breast cancer cells and mechanism of cytotoxic action.

Chemodynamic therapy (CDT) has received more and more attention as an emerging therapeutic strategy, especially transition metals with Fenton or Fenton-like activity have good effects in CDT research, manganese dioxide nanosheets (MnO2 NSs) and their complexes have become one of the most favored nanomaterials in CDT of tumors. CDT is mainly based on the role of reactive oxygen species (ROS) in tumor treatment, which have clear chemical properties and produce clear chemical reactions. However, their mechanism of interaction with cells has not been fully elucidated. Here, we performed CDT on mouse breast cancer cells (4T1) based on MnO2 NSs, extracted the metabolites from the 4T1 cells during the treatment, and analyzed the differences in metabolites by using high-resolution liquid chromatography-mass spectrometry (LC-MS). Untargeted metabolomics studies were conducted using the relevant data. This study mainly explored the changes in MnO2 NSs on the metabolite profile of 4T1 cells and their potential impact on tumor therapy, in order to determine the mechanism of action of MnO2 NSs in the treatment of breast cancer. The results of the study showed the presence of 11 different metabolites in MnO2 NSs CDT for 4T1 tumor cells, including phosphoserine, sphingine, phosphocholine, and stearoylcarnitine. These findings provide a deeper understanding of breast cancer treatment, and are beneficial for the further research and clinical application of CDT.

Characterization of Tumor Mutation Burden-Based Gene Signature and Molecular Subtypes to Assist Precision Treatment in Gastric Cancer.

Objective: Tumor mutation burden (TMB) represents a useful biomarker for predicting survival outcomes and immunotherapy response. Here, we aimed to conduct TMB-based gene signature and molecular subtypes in gastric cancer. Methods: Based on differentially expressed genes (DEGs) between high- and low-TMB groups in TCGA, a LASSO model was developed for predicting overall survival (OS) and disease-free survival (DFS). The predictive performance was externally verified in the GSE84437 dataset. Molecular subtypes were conducted via consensus clustering approach based on TMB-related DEGs. The immune microenvironment was estimated by ESTIMATE and ssGSEA algorithms. Results: High-TMB patients had prolonged survival duration. TMB-related DEGs were distinctly enriched in cancer- (MAPK, P53, PI3K-Akt, and Wnt pathways) and immune-related pathways (T cell selection and differentiation). The TMB-based gene model was developed (including MATN3, UPK1B, GPX3, and RGS2), and high-risk score was predictive of poor prognosis and recurrence. ROC and multivariate analyses revealed the well predictive performance, which was confirmed in the external cohort. Furthermore, we established the nomogram containing the risk score, age, and stage for personalized prediction of OS and DFS. High-risk score was characterized by high stromal score, increased immune checkpoints, immune cell infiltrations, and enhanced sensitivity to gefitinib, vinorelbine, and gemcitabine. Three TMB-based molecular subtypes were conducted, characterized by distinct prognosis, immune microenvironment, and drug sensitivity. Conclusion: Collectively, we established a prognostic signature and three distinct molecular subtypes based on TMB features for gastric cancer, which might be beneficial for prognostic prediction and clinical decision-making.

Incidence and risk factors for postoperative pancreatic fistula in 2089 patients treated by radical gastrectomy: A prospective multicenter cohort study in China.

OBJECTIVE: To determine the incidence of clinically relevant postoperative pancreatic fistula (CR-POPF) following radical gastrectomy and to identify independent risk factors of CR-POPF. BACKGROUND: CR-POPF and its sequelae are potential complications following radical gastrectomy. The reported incidence of CR-POPF was quite different across various regions, and no consensus was reached. METHODS: Between December 2017 to November 2018, patients who underwent radical gastrectomy from 22 centers across 13 regions in China were prospectively recruited. The primary endpoint was the occurrence of CR-POPF, defined by the International Study Group of Pancreatic Fistula (ISGPF) in 2016. Clinically relevant change and short-term outcomes were recorded to diagnose and grade the POPF. Multivariate regression analyses were performed to identify independent risk factors of clinically relevant postoperative pancreatic fistula (CR-POPF). RESULTS: A total of 2089 cases were analyzed. The incidence of biochemical leakage (BL) and CR-POPF were 19.6% and 1.1% respectively. All CR-POPF patients recovered well after appropriate treatment and no Grade C POPF were recorded. Logistic regression analysis showed pTNM III (OR, 2.940; 95% CI 1.180-7.325; P = 0.021) and LigaSure usage (OR, 6.618; 95% CI 1.847-23.707; P = 0.004) were independent risk factors of CR-POPF. LigaSure usage (OR, 4.817; 95% CI 1.184-19.598; P = 0.028), the drain amylase content (D-AMY) on postoperative day 3 (POD3) ≥5 times the upper limit of normal amylase (OR, 3.476; 95% CI 1.240-9.744; P = 0.018) and open surgery (OR, 2.463; 95% CI 1.003-6.050; P = 0.049) were independent predictors for identifying CR-POPF from BL. CONCLUSION: In rich-experienced gastric cancer centers, there is high prevalence of BL secondary to radical gastrectomy without clinical impact. Fewer patients suffered Grade B POPF, and Grade C POPF was less common. The patients with pTNM III or LigaSure usage were prone to suffer CR-POPF. Surgery procedure, LigaSure usage combined with D-AMY measurement on POD3 are promising for early identification of CR-POPF.

Prognostic Significance of Preoperative Serum Carcinoembryonic Antigen Varies with Lymph Node Metastasis Status in Colorectal Cancer.

BACKGROUND: Preoperative serum level of carcinoembryonic antigen (pCEA) is generally recognized as a prognostic factor for colorectal cancer (CRC), but the stage-specific role of pCEA in colorectal cancer remains unclear. OBJECTIVE: We investigated the prognostic significance of pCEA levels in different tumor stages of nonmetastatic CRC patients. METHODS: Six hundred and fifteen CRC patients at stage I-III were retrospectively analyzed. All of them received curative tumor resection. The X-tile program was used to generate stage-specific cutoff values of pCEA for all patients and two subpopulations (lymph node-positive or -negative). The prognostic significance of pCEA was assessed using Kaplan-Meier analysis and Cox proportional hazards regression analysis. A nomogram model that combined pCEA score and clinical feature indexes was established and evaluated. RESULTS: Two cutoff values were identified in the study population. At a cutoff value of 4.9 ng/mL, a significantly higher 5-year overall survival (OS) rate (82.16%) was observed in the pCEA-low group (<4.9 ng/mL) compared with 65.52% in the pCEA-high group (≥4.9 ng/mL). Furthermore, at the second cutoff value of 27.2 ng/mL, 5-year OS was found to be only 40.9%. Stratification analysis revealed that preoperative serum level of pCEA was an independent prognostic factor (OR = 1.991, P < 0.01) in the subpopulation of lymph node metastasis (stage III) patients, and the relative survival rates in the pCEA-low (≤4.9 ng/mL), pCEA-medium (4.9-27.2 ng/mL), and pCEA-high (≥27.2 ng/mL) groups were 73.4%, 60.5%, and 24.8%, respectively (P < 0.05). However, no such effect was observed in the lymph node nonmetastasis (stage I and II) subgroup. The established nomogram showed acceptable predictive power of the 5-year OS rate (C-index: 0.612) in lymph node-positive CRC patients, with an area under the curve value of 0.772, as assessed by ROC curve analysis. CONCLUSIONS: Pretreatment serum CEA levels had different prognostic significance based on the lymph node metastasis status. Among stage III CRC patients, pCEA was an independent prognostic factor. Five-year OS rates could be predicted according to the individual pCEA level at the different cutoff values.

Genetic and functional analysis reveals TENM4 contributes to schizophrenia.

TENM4, encoding a member of the teneurin protein family, is a risk gene shared by many types of mental diseases and is implicated in neuronal plasticity and signaling. However, the role and the mechanisms of TENM4 in schizophrenia (SCZ) remain unclear. We identified possible pathogenic mutations in the TENM4 gene through target sequencing of TENM4 in 68 SCZ families. We further demonstrated that aberrant expression of Ten-m leads to lower learning ability, sleep reduction, and increased aggressiveness in animal models. RNA sequencing showed that aberrant expression of Ten-m was related to stimulus perception and metabolic process, and Gene Ontology enrichment terms were neurogenesis and ATPase activity. This study provides strong evidence that TENM4 contributes to SCZ, and its functional mutations might be responsible for the impaired neural circuits and behaviors observed in SCZ.

Suboptimal adaptive Kalman filtering based on the proportional control of prior error covariance.

For linear time-invariant systems, this paper develops a new kind of adaptive Kalman filter to deal with Kalman filtering problems troubled by unknown/inaccurate process noise covariance. The limitation of Kalman filter is that its performance would deteriorate or even degrade if the accurate noise statistics could not be obtained in advance. To reduce or mitigate the negative influence caused by unknown/mismatched process noise covariance, this work elaborates a novel covariance control scheme in which the prior error covariance is recursively regulated with the proportional form of feedback information: the posterior sequence is first evaluated as online feedback to constitute a closed-loop structure for covariance propagation process, and then a proportional gain is employed to amplify the feedback term and fasten the converging of the estimated covariance parameter; note that, the new approach is relatively more independent of the parameter of process noise covariance and, therefore, the Kalman theory's rigorous dependency on accurate process noise covariance could be relaxed significantly. The mathematical properties and sub-optimality of the new covariance control scheme are discussed in detail as well as some practical considerations. The advantage of this newly developed method in filtering accuracy, adaptability and simplicity are illustrated with an object tracking scenario.

Contribution of Social Influences through Superposition of Visual and Olfactory Inputs to Circadian Re-entrainment.

Circadian patterns of locomotor activity are influenced by social interactions. Studies on insects highlight the importance of volatile odors and the olfactory system. Wild-type Drosophila exhibit immediate re-entrainment to new light:dark (LD) cycles, whereas cryb and jetc mutants show deficits in re-entrainability. We found that both male mutants re-entrained faster to phase-shifted LD cycles when social interactions with WT female flies were promoted than the isolated males. In addition, we found that accelerated re-entrainment mediated by social interactions depended on both visual and olfactory cues, and the effect of both cues presented jointly was nearly identical to the sum of the effects of the two cues presented separately. Moreover, we found that re-entrainment deficits in period (per) expression-oscillation in jetc mutants were partially restored by promoting social interactions. Our results demonstrated that, in addition to olfaction, social interactions through the visual system also play important roles in clock entrainment.