Irinotecan plus raltitrexed as second­line chemotherapy for metastatic colorectal cancer: A retrospective study.

The present study evaluated the efficiency, prognostic factors for and the safety of irinotecan combined with raltitrexed (TOMIRI) in patients with metastatic colorectal cancer (CRC). Outcome data of patients who received TOMIRI as first-, second- and third- or later-line treatment regimens were assessed to compare the efficacy of this regimen. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and disease control rate (DCR) were evaluated for each group. Kaplan-Meier curves and univariate and multivariate analyses were performed to evaluate efficacy. From January 2017 to December 2019, TOMIRI was administered as a first-line treatment in 23 patients, second-line treatment in 164 patients and third- or later-line treatment in 18 patients. Irinotecan and 5-fluorouracil (FOLFIRI) was administered to another 50 patients, who served as the control group. The median PFS was 9, 7 and 6 months and the median OS was 37, 21 and 17 months for first-, second- and third- or later-line treatments, respectively. The ORRs of the included patients were 21.7, 13.4 and 11.1%, respectively, and the DCRs were 91.3, 81.7 and 66.7%, respectively. Compared with FOLFIRI, TOMIRI as a second-line chemotherapy treatment was associated with longer survival of the patients with CRC. Further analysis demonstrated that pathologic tumor-node-metastasis category, carcinoembryonic antigen, carbohydrate antigen 19-9, treatment cycles, targeted therapy, treatment of local metastases and first-line PFS were prognostic factors for second-line treatment. Among these, the number of treatment cycles was of vital importance. Hepatic dysfunction was the most commonly reported grade 1-2 (55.1%) and grade 3-4 (7.3%) adverse event. Neutropenia (12.2%), thrombocytopenia (10.2%), anemia (27.3%), proteinuria (38.1%) and hematuria (21.0%) were also common grade 1-2 adverse events. In conclusion, TOMIRI may be recommended as an effective and safe second-line treatment for metastatic CRC in the clinic.

Comparative Study of Bacterial Microbiota Differences in the Rumen and Feces of Xinjiang Brown and Holstein Cattle.

Xinjiang Brown cattle are a unique and widely distributed breed of dual-purpose cattle in the Xinjiang area of China, whose milk production performance differs from Holstein cattle. It has been known that variations in bacterial species of the gastrointestinal tract influence milk protein, fat, and lactose synthesis. However, the microbiota differences between Xinjiang Brown and Holstein cattle are less known. This study aims to compare the bacterial community composition of the rumen and feces of these two cattle breeds under the same dietary and management conditions. The 16s rRNA sequencing data and milk production of 18 Xinjiang Brown cows and 20 Holstein cows on the same farm were obtained for analysis. The results confirmed differences in milk production between Xinjiang Brown and Holstein cattle. Microbiota with different relative abundance between these two cattle breeds were identified, and their biological functions might be related to milk synthesis. This study increases the understanding of the differences in microbiota between Xinjiang Brown and Holstein cattle and might provide helpful information for microbiota composition optimization of these dairy cattle.

A Visual Measurement Method for Deep Holes in Composite Material Aerospace Components.

The visual measurement of deep holes in composite material workpieces constitutes a critical step in the robotic assembly of aerospace components. The positioning accuracy of assembly holes significantly impacts the assembly quality of components. However, the complex texture of the composite material surface and mutual interference between the imaging of the inlet and outlet edges of deep holes significantly challenge hole detection. A visual measurement method for deep holes in composite materials based on the radial penalty Laplacian operator is proposed to address the issues by suppressing visual noise and enhancing the features of hole edges. Coupled with a novel inflection-point-removal algorithm, this approach enables the accurate detection of holes with a diameter of 10 mm and a depth of 50 mm in composite material components, achieving a measurement precision of 0.03 mm.

Genomic prediction based on a joint reference population for the Xinjiang Brown cattle.

Introduction: Xinjiang Brown cattle constitute the largest breed of cattle in Xinjiang. Therefore, it is crucial to establish a genomic evaluation system, especially for those with low levels of breed improvement. Methods: This study aimed to establish a cross breed joint reference population by analyzing the genetic structure of 485 Xinjiang Brown cattle and 2,633 Chinese Holstein cattle (Illumina GeneSeek GGP bovine 150 K chip). The Bayes method single-step genome-wide best linear unbiased prediction was used to conduct a genomic evaluation of the joint reference population for the milk traits of Xinjiang Brown cattle. The reference population of Chinese Holstein cattle was randomly divided into groups to construct the joint reference population. By comparing the prediction accuracy, estimation bias, and inflation coefficient of the validation population, the optimal number of joint reference populations was determined. Results and Discussion: The results indicated a distinct genetic structure difference between the two breeds of adult cows, and both breeds should be considered when constructing multi-breed joint reference and validation populations. The reliability range of genome prediction of milk traits in the joint reference population was 0.142-0.465. Initially, it was determined that the inclusion of 600 and 900 Chinese Holstein cattle in the joint reference population positively impacted the genomic prediction of Xinjiang Brown cattle to certain extent. It was feasible to incorporate the Chinese Holstein into Xinjiang Brown cattle population to form a joint reference population for multi-breed genomic evaluation. However, for different Xinjiang Brown cattle populations, a fixed number of Chinese Holstein cattle cannot be directly added during multi-breed genomic selection. Pre-evaluation analysis based on the genetic structure, kinship, and other factors of the current population is required to ensure the authenticity and reliability of genomic predictions and improve estimation accuracy.

Error Analysis of Normal Surface Measurements Based on Multiple Laser Displacement Sensors.

The robotic drilling of assembly holes is a crucial process in aerospace manufacturing, in which measuring the normal of the workpiece surface is a key step to guide the robot to the correct pose and guarantee the perpendicularity of the hole axis. Multiple laser displacement sensors can be used to satisfy the portable and in-site measurement requirements, but there is still a lack of accurate analysis and layout design. In this paper, a simplified parametric method is proposed for multi-sensor normal measurement devices with a symmetrical layout, using three parameters: the sensor number, the laser beam slant angle, and the laser spot distribution radius. A normal measurement error distribution simulation method considering the random sensor errors is proposed. The measurement error distribution laws at different sensor numbers, the laser beam slant angle, and the laser spot distribution radius are revealed as a pyramid-like region. The influential factors on normal measurement accuracy, such as sensor accuracy, quantity and installation position, are analyzed by a simulation and verified experimentally on a five-axis precision machine tool. The results show that increasing the laser beam slant angle and laser spot distribution radius significantly reduces the normal measurement errors. With the laser beam slant angle ≥15° and the laser spot distribution radius ≥19 mm, the normal measurement error falls below 0.05°, ensuring normal accuracy in robotic drilling.

Biodiversity mitigates drought effects in the decomposer system across biomes.

Multiple facets of global change affect the earth system interactively, with complex consequences for ecosystem functioning and stability. Simultaneous climate and biodiversity change are of particular concern, because biodiversity may contribute to ecosystem resistance and resilience and may mitigate climate change impacts. Yet, the extent and generality of how climate and biodiversity change interact remain insufficiently understood, especially for the decomposition of organic matter, a major determinant of the biosphere-atmosphere carbon feedbacks. With an inter-biome field experiment using large rainfall exclusion facilities, we tested how drought, a common prediction of climate change models for many parts of the world, and biodiversity in the decomposer system drive decomposition in forest ecosystems interactively. Decomposing leaf litter lost less carbon (C) and especially nitrogen (N) in five different forest biomes following partial rainfall exclusion compared to conditions without rainfall exclusion. An increasing complexity of the decomposer community alleviated drought effects, with full compensation when large-bodied invertebrates were present. Leaf litter mixing increased diversity effects, with increasing litter species richness, which contributed to counteracting drought effects on C and N loss, although to a much smaller degree than decomposer community complexity. Our results show at a relevant spatial scale covering distinct climate zones that both, the diversity of decomposer communities and plant litter in forest floors have a strong potential to mitigate drought effects on C and N dynamics during decomposition. Preserving biodiversity at multiple trophic levels contributes to ecosystem resistance and appears critical to maintain ecosystem processes under ongoing climate change.

[Cloning and functional analysis of flavanone synthase â ¡ from Dendrobium huoshanense].

Flavonoid C-glycosides are a class of natural products that are widely involved in plant defense responses and have diverse pharmacological activities. They are also important active ingredients of Dendrobium huoshanense. Flavanone synthase Ⅱ has been proven to be a key enzyme in the synthesis pathway of flavonoid C-glycosides in plants, and their catalytic product 2-hydroxyflavanone is the precursor compound for the synthesis of various reported flavonoid C-glycosides. In this study, based on the reported amino acid sequence of flavanone synthase Ⅱ, a flavanone synthase Ⅱ gene(DhuFNSⅡ) was screened and verified from the constructed D. huoshanense genome localization database. Functional validation of the enzyme showed that it could in vitro catalyze naringenin and pinocembrin to produce apigenin and chrysin, respectively. The open reading frame(ORF) of DhuFNSⅡ was 1 644 bp in length, encoding 547 amino acids. Subcellular localization showed that the protein was localized on the endoplasmic reticulum. RT-qPCR results showed that DhuFNSⅡ had the highest expression in stems, followed by leaves and roots. The expression levels of DhuFNSⅡ and other target genes in various tissues of D. huoshanense were significantly up-regulated after four kinds of abiotic stresses commonly encountered in the growth process, but the extent of up-regulation varied among treatment groups, with drought and cold stress having more significant effects on gene expression levels. Through the identification and functional analysis of DhuFNSⅡ, this study is expected to contribute to the elucidation of the molecular mechanism of the formation of quality metabolites of D. huoshanense, flavonoid C-glycosides, and provide a reference for its quality formation and scientific cultivation.

Identification of colon cancer subtypes based on multi-omics data-construction of methylation markers for immunotherapy.

Background: Being the most widely used biomarker for immunotherapy, the microsatellite status has limitations in identifying all patients who benefit in clinical practice. It is essential to identify additional biomarkers to guide immunotherapy. Aberrant DNA methylation is consistently associated with changes in the anti-tumor immune response, which can promote tumor progression. This study aims to explore immunotherapy biomarkers for colon cancers from the perspective of DNA methylation. Methods: The related data (RNA sequencing data and DNA methylation data) were obtained from The Cancer Genome Atlas (TCGA) and UCSC XENA database. Methylation-driven genes (MDGs) were identified through the Pearson correlation analysis. Unsupervised consensus clustering was conducted using these MDGs to identify distinct clusters of colon cancers. Subsequently, we evaluated the immune status and predicted the efficacy of immunotherapy by tumor immune dysfunction and exclusion (Tide) score. Finally, The Quantitative Differentially Methylated Regions (QDMR) software was used to identify the specific DNA methylation markers within particular clusters. Results: A total of 282 MDGs were identified by integrating the DNA methylation and RNA-seq data. Consensus clustering using the K-means algorithm revealed that the optimal number of clusters was 4. It was revealed that the composition of the tumor immune microenvironment (TIME) in Cluster 1 was significantly different from others, and it exhibited a higher level of tumor mutation burdens (TMB) and stronger anti-tumor immune activity. Furthermore, we identified three specific hypermethylation genes that defined Cluster 1 (PCDH20, APCDD1, COCH). Receiver operating characteristic (ROC) curves demonstrated that these specific markers could effectively distinguish Cluster 1 from other clusters, with an AUC of 0.947 (95% CI 0.903-0.990). Finally, we selected clinical samples for immunohistochemical validation. Conclusion: In conclusion, through the analysis of DNA methylation, consensus clustering of colon cancer could effectively identify the cluster that benefit from immunotherapy along with specific methylation biomarkers.

Clinical Implications of Naples Prognostic Score for Patients with Resected Cholangiocarcinoma: A Real-World Experience.

Purpose: The Nutritional Prognostic Score (NPS) is a composite indicator that effectively reflects the preoperative nutritional and inflammation status of patients. Its prognostic value has been extensively confirmed in various types of tumors. Our study aims to investigate the clinical implications of the NPS in the postoperative patients with cholangiocarcinoma (CCA). Patients and Methods: Data on clinicopathological characteristics were collected from CCA patients who underwent radical surgery between 2014 and 2019 at Harbin Medical University Cancer Hospital. NPS was calculated using relevant indicators to categorize the patients, and association of NPS with clinicopathological characteristics and survival outcomes were analyzed. To assess differences in survival rates between different groups, we utilized the Kaplan-Meier method. Independent prognostic risk factors were identified by Cox regression analysis. A CONomogram was created, and its accuracy in survival prediction was evaluated using receiver operating characteristic (ROC) curves. Independent verification was conducted in the validation group. Results: For this study, a cohort of 232 patients was enlisted and subsequently divided into training group (N=162) and validation group (N=70). An evident correlation was detected between NPS and preoperative malnutrition. Patients with higher NPS exhibited a worse overall survival (OS), with 5-year OS rates of 79.1%, 33.1%, and 10.6%. Multivariate analysis revealed that NPS was an independent risk factor for OS in resected CCA patients (P<0.001). The NPS-based Nomogram was developed to accurately assess the risk of patients. Conclusion: The NPS was identified as a significant risk factor that impacts the prognosis of patients with resected CCA. In order to improve prognosis management, the NPS-based Nomogram has been demonstrated to be a precise and efficient tool.

Output-Feedback Consensus Maneuvering of Uncertain MIMO Strict-Feedback Multiagent Systems Based on a High-Order Neural Observer.

In this article, a distributed output-feedback consensus maneuvering problem is investigated for a class of uncertain multiagent systems with multi-input and multi-output (MIMO) strict-feedback dynamics. The followers are subject to immeasurable states and external disturbances. A distributed neural observer-based adaptive control method is designed for consensus maneuvering of uncertain MIMO multiagent systems. The method is based on a modular structure, resulting in the separation of three modules: 1) a variable update law for the parameterized path; 2) a high-order neural observer; and 3) an output-feedback consensus maneuvering control law. The proposed distributed neural observer-based adaptive control method ensures that all followers agree on a common motion guided by a desired parameterized path, and the proposed method evades adopting the adaptive backstepping or dynamic surface control design by reformulating the dynamics of agents, thereby reducing the complexity of the control structure. Combined with the cascade system analysis and interconnection system analysis, the input-to-state stability of the consensus maneuvering closed loop is established in the Lyapunov sense. A simulation example is presented to demonstrate the performance of the proposed distributed neural observer-based adaptive control method for output-feedback consensus maneuvering.

Racial Disparities in Accessing Care along the Continuum of Cancer Genetic Service Delivery.

BACKGROUND: Public health calls to ensure equity in genomics and precision medicine necessitate a closer examination of how these efforts might differentially affect access to genetic services across demographic subgroups. This study set out to examine racial/ethnic disparities along the cancer genetic service delivery continuum. METHODS: Retrospective data are drawn from 15 clinical sites across 6 U.S. States. Individuals who screened at-risk for hereditary cancer were: (i) referred/scheduled to see a genetic counselor (referral workflow), or (ii) offered genetic testing at the point-of-care (POC testing workflow). Logistic regression analyses evaluated the associations between race/ethnicity and several outcomes including appointment scheduling, genetic counseling, and genetic testing, controlling for demographics, clinical factors, and county-level covariates. RESULTS: A total of 14,527 patients were identified at-risk. Genetic testing uptake was significantly higher at POC sites than referral sites (34% POC vs. 11% referral, P < 0.001). Race/ethnicity was significantly associated with testing uptake among all sites, with non-Hispanic Blacks having lower odds of testing compared with non-Hispanic Whites [aOR = 0.84; 95% confidence interval (CI), 0.71-1.00; P = 0.049]. Moreover, this disparity was observed at referral sites, but not POC sites. Among patients scheduled, non-Hispanic Blacks had lower odds of counseling (aOR = 0.28; 95% CI, 0.17-0.47; P < 0.001). CONCLUSIONS: Findings suggest that factors influencing genetic counseling show rates may be driving disparities in genetic testing. IMPACT: Strategies to reduce barriers to seeing a genetic counselor, including modifications to clinical workflow, may help mitigate racial/ethnic disparities in genetic testing.

Chloroplast genome of Justicia procumbens: genomic features, comparative analysis, and phylogenetic relationships among Justicieae species.

Justicia procumbens L. is a traditional medicinal plant that is widely distributed in China. However, little is known about the genetic diversity and evolution of this genus, and no genomic studies have been carried out on J. procumbens previously. In this study, we aimed to assemble and annotate the first complete chloroplast genome (cpDNA) of J. procumbens and compare it with all previously published cpDNAs within the tribe Justicieae. Genome structure and comparative and phylogenetic analyses were performed. The 150,454 bp-long J. procumbens cpDNA has a circular and quadripartite structure consisting of a large single copy, a small single copy, and two inverted repeat regions. It contains 133 genes, of which 88 are protein-coding genes, 37 are tRNA genes, and eight are rRNA genes. Twenty-four simple sequence repeats (SSRs) and 81 repeat sequences were identified. Comparative analyses with other Justicieae species revealed that the non-coding regions of J. procumbens cpDNA showed greater variation than did the coding regions. Moreover, phylogenetic analysis based on 14 cpDNA sequences from Justicieae species showed that J. procumbens and J. flava were most closely related. This study provides valuable genetic information to support further research on the genetic diversity and evolutionary development of the tribe Justicieae.

Dynamic monitoring of serum CEA and CA19-9 predicts the prognosis of postoperative stage II colon cancer.

BACKGROUND: We sought to investigate the prognostic significance of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) dynamics for stage II colon cancer patients undergoing radical resection. METHODS: This study retrospectively analyzed 1517 stage II colon cancer patients admitted to the Harbin Medical University Cancer Hospital from January 2011 to December 2016. To observe the relationship between tumor markers dynamic monitoring and survival, we calculated cut-off values for ΔCEA and ΔCA19-9. Group according to the cut-off values and compare the differences in survival between subgroups. RESULTS: Preoperative CA199 (HR = 3.122), postoperative CEA (HR = 2.941) and histological type (HR = 2.855) were independent prognostic factors in multivariate Cox proportional hazards models. The 5-year overall survival (OS) in the patients with normal preoperative CEA and CA19-9 was significantly better than the patients with elevated preoperative CEA or CA19-9 and the patients with elevated preoperative CEA and CA19-9 (92.6 % vs. 87.6 % vs. 81.0 %, P < 0.05). 469 patients with normal pre- and post-operative CEA had the highest 5-year OS (93.5 %, P < 0.05). Among the 177 patients with elevated pre- and post-operative CEA, the 5-year OS rate was only 81.8 % (P < 0.05). The cut-off values for Δ CEA and Δ CA19-9 in stage II colon cancer patients with elevated preoperative tumor markers were 2.625 ng/ml and 7.835 U/ml, respectively. The Kaplan-Meier curves showed that Δ CEA≥2.625 ng/ml and Δ CA19-9≥7.835 U/mL were associated with better outcome (87.8 % vs. 79.6 %, P < 0.05; 85.8 % vs. 79.1 %, P > 0.05). At the same time, we found that adjuvant chemotherapy significantly improved 5-year OS in patients with elevated preoperative CEA or CA19-9 (91.0 % vs. 80.9 % and 89.6 % vs. 80.2 %, P < 0.05). CONCLUSIONS: Persistent postoperative elevation of CEA/CA19-9 is associated with a poor prognosis. CEA and CA19-9 may be high-risk factors for postoperative adjuvant therapy in stage II colon cancer patients. For stage II colon cancer patients with elevated preoperative CEA, patients with Δ CEA<2.625 ng/ml have poor survival and can improve prognosis by receiving adjuvant therapy.

Unraveling temporal and spatial biomarkers of epithelial-mesenchymal transition in colorectal cancer: insights into the crucial role of immunosuppressive cells.

The occurrence and progression of tumors can be established through a complex interplay among tumor cells undergoing epithelial-mesenchymal transition (EMT), invasive factors and immune cells. In this study, we employed single-cell RNA sequencing (scRNA-seq) and spatially resolved transcriptomics (ST) to evaluate the pseudotime trajectory and spatial interactive relationship between EMT-invasive malignant tumors and immune cells in primary colorectal cancer (CRC) tissues at different stages (stage I/II and stage III with tumor deposit). Our research characterized the spatiotemporal relationship among different invasive tumor programs by constructing pseudotime endpoint-EMT-invasion tumor programs (EMTPs) located at the edge of ST, utilizing evolution trajectory analysis integrated with EMT-invasion genes. Strikingly, the invasive and expansive process of tumors undergoes remarkable spatial reprogramming of regulatory and immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), regulatory T cells (Treg), and exhausted T cells (Tex). These EMTP-adjacent cell are linked to EMT-related invasion genes, especially the C-X-C motif ligand 1 (CXCL1) and CXCL8 genes that are important for CRC prognosis. Interestingly, the EMTPs in stage I mainly produce an inflammatory margin invasive niche, while the EMTPs in stage III tissues likely produce a hypoxic pre-invasive niche. Our data demonstrate the crucial role of regulatory and immunosuppressive cells in tumor formation and progression of CRC. This study provides a framework to delineate the spatiotemporal invasive niche in CRC samples.

RNA-Seq Analysis of Peripheral Whole Blood from Dairy Bulls with High and Low Antibody-Mediated Immune Responses-A Preliminary Study.

Enhancing the immune response through breeding is regarded as an effective strategy for improving animal health, as dairy cattle identified as high immune responders are reported to have a decreased prevalence of economically significant diseases. The identification of differentially expressed genes (DEGs) associated with immune responses might be an effective tool for breeding healthy dairy cattle. In this study, antibody-mediated immune responses (AMIRs) were induced by the immunization of hen egg white lysozyme (HEWL) in six Chinese Holstein dairy bulls divided into high- and low-AMIR groups based on their HEWL antibody level. Then, RNA-seq was applied to explore the transcriptome of peripheral whole blood between the two comparison groups. As a result, several major upregulated and downregulated genes were identified and attributed to the regulation of locomotion, tissue development, immune response, and detoxification. In addition, the result of the KEGG pathway analysis revealed that most DEGs were enriched in pathways related to disease, inflammation, and immune response, including antigen processing and presentation, Staphylococcus aureus infection, intestinal immune network for IgA production, cytokine-cytokine receptor interaction, and complement and coagulation cascades. Moreover, six genes (BOLA-DQA5, C5, CXCL2, HBA, LTF, and COL1A1) were validated using RT-qPCR, which may provide information for genomic selection in breeding programs. These results broaden the knowledge of the immune response mechanism in dairy bulls, which has strong implications for breeding cattle with an enhanced AMIR.

Role of endogenous and exogenous antioxidants in risk of six cancers: evidence from the Mendelian randomization study.

Background: Although oxidative stress is known to contribute to cancer, and endogenous and exogenous antioxidants are thought to prevent tumorigenesis by suppressing oxidative stress-induced DNA damage, antioxidants have also been reported to show negative effects on tumor formation, necessitating characterization of the causal associations between antioxidants and cancer risk. Methods: In this study, Mendelian randomization (MR) analysis, primarily inverse-variance weighted MR, was used to assess the causal effect of six endogenous and five exogenous diet-derived antioxidants on the risk of six cancers. MR-Egger intercept test and Cochran's Q statistic were utilized to assess pleiotropy and heterogeneity, respectively. Results: For endogenous antioxidants, a bidirectional two-sample MR analysis was conducted. Our findings suggested that serum albumin has a negative causal association with the risk of prostate cancer [odds ratio (OR) = 0.78, 95% confidence interval (CI): 0.68-0.91, p = 0.001]. The risks of the six cancers showed no significant associations with endogenous antioxidants in the converse MR analysis. For exogenous antioxidants, the unidirectional two-sample MR analysis exhibited a nominal relationship between the serum retinol level and non-small-cell lung cancer risk (OR = 0.29, 95% CI: 0.11-0.76, p = 0.011). Conclusions: Thus, our study revealed the protective effects of genetic susceptibility to high circulating albumin levels on prostate cancer, providing potential targeted interventions for prostate cancer prevention.

Esketamine is neuroprotective against traumatic brain injury through its modulation of autophagy and oxidative stress via AMPK/mTOR-dependent TFEB nuclear translocation.

Recent clinical studies highlight the neuroprotective effects of esketamine, but its benefits following traumatic brain injury (TBI) have not been defined. Here, we investigated the effects of esketamine following TBI and its associated neuroprotection mechanisms. In our study, controlled cortical impact injury on mice was utilized to induce the TBI model in vivo. TBI mice were randomized to receive vehicle or esketamine at 2 h post-injury for 7 consecutive days. Neurological deficits and brain water content in mice were detected, respectively. Cortical tissues surrounding focal trauma were obtained for Nissl staining, immunofluorescence, immunohistochemistry, and ELISA assay. In vitro, esketamine were added in culture medium after cortical neuronal cells induced by H2O2 (100µM). After exposed for 12h, neuronal cells were obtained for western blotting, immunofluorescence, ELISA and CO-IP assay. Following administration of 2-8 mg/kg esketamine, we observed that 8 mg/kg esketamine produced no additional recovery of neurological function and ability to alleviate brain edema in TBI mice model, so 4 mg/kg esketamine was selected for subsequent experiments. Additionally, esketamine can effectively reduce TBI-induced oxidative stress, the number of damaged neurons, and the number of TUNEL-positive cells in the cortex of TBI models. Meanwhile, the levels of Beclin 1, LC3 II, and the number of LC3-positive cells in injured cortex were also increased following esketamine exposure. Western blotting and immunofluorescence assays showed that esketamine accelerated the nuclear translocation of TFEB, increased the p-AMPKα level and decreased the p-mTOR level. Similar results including nuclear translocation of TFEB, the increases of autophagy-related markers, and influences of AMPK/mTOR pathway were observed in H2O2-induced cortical neuronal cells; however, BML-275 (AMPK inhibitor) can reverse these effects of esketamine. Furthermore, TFEB silencing not only decreased the Nrf2 level in H2O2-induced cortical neuronal cells, but also alleviated the oxidative stress. Importantly, CO-IP confirmed the interaction between TFEB and Nrf2 in cortical neuronal cells. These findings suggested that esketamine exerts the neuroprotective effects of esketamine in TBI mice model via enhancing autophagy and alleviating oxidative stress; its mechanism involves AMPK/mTOR-dependent TFEB nuclear translocation-induced autophagy and TFEB/Nrf2-induced antioxidant system.

Stomatal responses of terrestrial plants to global change.

Quantifying the stomatal responses of plants to global change factors is crucial for modeling terrestrial carbon and water cycles. Here we synthesize worldwide experimental data to show that stomatal conductance (gs) decreases with elevated carbon dioxide (CO2), warming, decreased precipitation, and tropospheric ozone pollution, but increases with increased precipitation and nitrogen (N) deposition. These responses vary with treatment magnitude, plant attributes (ambient gs, vegetation biomes, and plant functional types), and climate. All two-factor combinations (except warming + N deposition) significantly reduce gs, and their individual effects are commonly additive but tend to be antagonistic as the effect sizes increased. We further show that rising CO2 and warming would dominate the future change of plant gs across biomes. The results of our meta-analysis provide a foundation for understanding and predicting plant gs across biomes and guiding manipulative experiment designs in a real world where global change factors do not occur in isolation.

Implementing digital systems to facilitate genetic testing for hereditary cancer syndromes: An observational study of 4 clinical workflows.

PURPOSE: National efforts have prioritized the identification of effective methods for increasing case ascertainment and delivery of evidence-based health care for individuals at elevated risk for hereditary cancers. METHODS: This study examined the uptake of genetic counseling and testing following the use of a digital cancer genetic risk assessment program implemented at 27 health care sites in 10 states using 1 of 4 clinical workflows: (1) traditional referral, (2) point-of-care scheduling, (3) point-of-care counseling/telegenetics, and (4) point-of-care testing. RESULTS: In 2019, 102,542 patients were screened and 33,113 (32%) were identified as at high risk and meeting National Comprehensive Cancer Network genetic testing criteria for hereditary breast and ovarian cancer, Lynch syndrome, or both. Among those identified at high risk, 5147 (16%) proceeded with genetic testing. Genetic counseling uptake was 11% among the sites with workflows that included seeing a genetic counselor before testing, with 88% of patients proceeding with genetic testing after counseling. Uptake of genetic testing across sites varied significantly by clinical workflow (6% referral, 10% point-of-care scheduling, 14% point-of-care counseling/telegenetics, and 35% point-of-care testing, P < .0001). CONCLUSION: Study findings highlight the potential heterogeneity of effectiveness attributable to different care delivery approaches for implementing digital hereditary cancer risk screening programs.

Survival rate of colorectal cancer in China: A systematic review and meta-analysis.

Background: This study aims to comprehensively summarize the colorectal survival rate in China. Method: In PubMed and Web of Science, keywords such as "colorectal cancer", "survival" and "China" were used to search literatures in the past 10 years. Random effect models were selected to summarize 1-year, 3-year, and 5-year survival rates, and meta-regression and subgroup analyses were performed on the included studies. Results: A total of 16 retrospective and prospective studies providing survival rates for colorectal cancer in China were included. The 1-year, 3-year, and 5-year survival rates of colorectal cancer in China were 0.79, 0.72 and 0.62, respectively. In the included studies, the 5-year survival rates of stage I (5474 cases), stage II (9215 cases), stage III (8048 cases), and stage IV (4199 cases) colorectal cancer patients were 0.85, 0.81, 0.57 and 0.30, respectively. Among them, the 5-year survival rates of colorectal cancer were 0.82, 0.76, 0.71, 0.67, 0.66, 0.65 and 0.63 in Tianjin, Beijing, Guangdong, Shandong, Liaoning, Zhejiang and Shanghai, respectively. Conclusion: The 5-year survival rate in China is close to that of most European countries, but still lower than Japan and South Korea, and the gap is gradually narrowing. Region, stage, differentiation, pathological type, and surgical approach can affect 5-year survival in colorectal cancer. Systematic review registration: https://www.crd.york.ac.uk/prospero/ identifier, CRD42022357789.