Practical Application of Multivendor MRI-Based R2* Mapping for Liver Iron Quantification at 1.5 T and 3.0 T.

BACKGROUND: Recent multicenter, multivendor MRI-based R2* vs. liver iron concentration (LIC) calibrations (i.e., MCMV calibrations) may facilitate broad clinical dissemination of R2*-based LIC quantification. However, these calibrations are based on a centralized offline R2* reconstruction, and their applicability with vendor-provided R2* maps is unclear. PURPOSE: To determine R2* ranges of agreement between the centralized and three MRI vendors' R2* reconstructions. STUDY TYPE: Prospective. SUBJECTS: Two hundred and seven subjects (mean age 37.6 ± 19.6 years; 117 male) with known or suspected iron overload from four academic medical centers. FIELD STRENGTH/SEQUENCE: Standardized multiecho spoiled gradient echo sequence at 1.5 T and 3.0 T for R2* mapping and a multiple spin-echo sequence at 1.5 T for LIC quantification. MRI vendors: GE Healthcare, Philips Healthcare, and Siemens Healthineers. ASSESSMENT: R2* maps were generated using both the centralized and vendor reconstructions, and ranges of agreement were determined. R2*-LIC linear calibrations were determined for each site, field strength, and reconstruction and compared with the MCMV calibrations. STATISTICAL TESTS: Bland-Altman analysis to determine ranges of agreement. Linear regression, analysis of covariance F tests, and Tukey's multiple comparison testing to assess reproducibility of calibrations across sites and vendors. A P value <0.05 was considered significant. RESULTS: The upper limits of R2* ranges of agreement were approximately 500, 375, and 330 s-1 for GE, Philips, and Siemens reconstructions, respectively, at 1.5 T and approximately 700 and 800 s-1 for GE and Philips, respectively, at 3.0 T. Within the R2* ranges of agreement, vendor R2*-LIC calibrations demonstrated high reproducibility (no significant differences between slopes or intercepts; P ≥ 0.06) and agreed with the MCMV calibrations (overlapping 95% confidence intervals). DATA CONCLUSION: Based on the determined upper limits, R2* measurements obtained from vendor-provided R2* maps may be reliably and practically used to quantify LIC less than approximately 8-13 mg/g using the MCMV calibrations and similar acquisition parameters as this study. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 3.

High-Dimensional MR Reconstruction Integrating Subspace and Adaptive Generative Models.

OBJECTIVE: To develop a new method that integrates subspace and generative image models for high-dimensional MR image reconstruction. METHODS: We proposed a formulation that synergizes a low-dimensional subspace model of high-dimensional images, an adaptive generative image prior serving as spatial constraints on the sequence of "contrast-weighted" images or spatial coefficients of the subspace model, and a conventional sparsity regularization. A special pretraining plus subject-specific network adaptation strategy was proposed to construct an accurate generative-network-based representation for images with varying contrasts. An iterative algorithm was introduced to jointly update the subspace coefficients and the multi-resolution latent space of the generative image model that leveraged an recently proposed intermediate layer optimization technique for network inversion. RESULTS: We evaluated the utility of the proposed method for two high-dimensional imaging applications: accelerated MR parameter mapping and high-resolution MR spectroscopic imaging. Improved performance over state-of-the-art subspace-based methods was demonstrated in both cases. CONCLUSION: The proposed method provided a new way to address high-dimensional MR image reconstruction problems by incorporating an adaptive generative model as a data-driven spatial prior for constraining subspace reconstruction. SIGNIFICANCE: Our work demonstrated the potential of integrating data-driven and adaptive generative priors with canonical low-dimensional modeling for high-dimensional imaging problems.

Calpain as a Therapeutic Target for Hypoxic-Ischemic Encephalopathy.

Hypoxic-ischemic encephalopathy (HIE) is a complex pathophysiological process with multiple links and factors. It involves the interaction of inflammation, oxidative stress, and glucose metabolism, and results in acute and even long-term brain damage and impairment of brain function. Calpain is a family of Ca2+-dependent cysteine proteases that regulate cellular function. Calpain activation is involved in cerebral ischemic injury, and this involvement is achieved by the interaction among Ca2+, substrates, organelles, and multiple proteases in the neuronal necrosis and apoptosis pathways after cerebral ischemia. Many calpain inhibitors have been developed and tested in the biochemical and biomedical fields. This study reviewed the potential role of calpain in the treatment of HIE and related mechanism, providing new insights for future research on HIE.

Total versus proximal gastrectomy for proximal gastric cancer after neoadjuvant chemotherapy: a multicenter retrospective propensity score-matched cohort study.

BACKGROUND: This study aimed to analyze and compare the short-term and long-term outcomes of proximal gastrectomy (PG) and total gastrectomy (TG) in patients with locally advanced proximal gastric cancer (GC) following neoadjuvant chemotherapy (NACT). METHOD: A multicenter retrospective cohort study and propensity score matching (PSM) were employed. The authors examined 367 patients with proximal GC who received NACT followed by PG ( n =164) or TG ( n =203) at two Chinese medical institutions between December 2009 and December 2022. Clinical and pathological parameters, postoperative complications, and 5-year overall survival (OS) and recurrence-free survival (RFS) were compared between the two groups. The dissection status and metastasis rate of each lymph node station were assessed. RESULTS: After PSM, 80 patients were enrolled in both TG and PG group, and baseline characteristics were comparable between the groups (all P >0.05). The TG group had a higher total number of lymph nodes retrieved ( P <0.001) and longer operative time ( P =0.007) compared to the PG group. The incidence of Clavien-Dindo grade II or higher postoperative complications was similar between the TG group (21.3%, 17/80) and the PG group (17.5%, 14/80) ( P =0.689). The 5-year OS rates were 68.4 for the PG group and 66.0% for the TG group ( P =0.881), while the 5-year RFS rates were 64.8 and 61.9%, respectively ( P =0.571), with no statistically significant differences. Metastasis rates at lymph node stations #4d, #5, #6, and #12a were notably low in the TG group, with values of 2.74, 0.67, 1.33, and 1.74%, respectively. CONCLUSION: For proximal GC patients following NACT, PG maintains comparable curative potential and oncological efficacy to TG, making it a safe option.

pH-gated nanoparticles selectively regulate lysosomal function of tumour-associated macrophages for cancer immunotherapy.

Tumour-associated macrophages (TAMs), as one of the most abundant tumour-infiltrating immune cells, play a pivotal role in tumour antigen clearance and immune suppression. M2-like TAMs present a heightened lysosomal acidity and protease activity, limiting an effective antigen cross-presentation. How to selectively reprogram M2-like TAMs to reinvigorate anti-tumour immune responses is challenging. Here, we report a pH-gated nanoadjuvant (PGN) that selectively targets the lysosomes of M2-like TAMs in tumours rather than the corresponding organelles from macrophages in healthy tissues. Enabled by the PGN nanotechnology, M2-like TAMs are specifically switched to a M1-like phenotype with attenuated lysosomal acidity and cathepsin activity for improved antigen cross-presentation, thus eliciting adaptive immune response and sustained tumour regression in tumour-bearing female mice. Our findings provide insights into how to specifically regulate lysosomal function of TAMs for efficient cancer immunotherapy.

Critical Signaling Transduction Pathways and Intestinal Barrier: Implications for Pathophysiology and Therapeutics.

The intestinal barrier is a sum of the functions and structures consisting of the intestinal mucosal epithelium, mucus, intestinal flora, secretory immunoglobulins, and digestive juices. It is the first-line defense mechanism that resists nonspecific infections with powerful functions that include physical, endocrine, and immune defenses. Health and physiological homeostasis are greatly dependent on the sturdiness of the intestinal barrier shield, whose dysfunction can contribute to the progression of numerous types of intestinal diseases. Disorders of internal homeostasis may also induce barrier impairment and form vicious cycles during the response to diseases. Therefore, the identification of the underlying mechanisms involved in intestinal barrier function and the development of effective drugs targeting its damage have become popular research topics. Evidence has shown that multiple signaling pathways and corresponding critical molecules are extensively involved in the regulation of the barrier pathophysiological state. Ectopic expression or activation of signaling pathways plays an essential role in the process of shield destruction. Although some drugs, such as molecular or signaling inhibitors, are currently used for the treatment of intestinal diseases, their efficacy cannot meet current medical requirements. In this review, we summarize the current achievements in research on the relationships between the intestinal barrier and signaling pathways. The limitations and future perspectives are also discussed to provide new horizons for targeted therapies for restoring intestinal barrier function that have translational potential.

LncRNA CCAT2 promotes malignant progression of metastatic gastric cancer through regulating CD44 alternative splicing.

OBJECTIVE: Gastric cancer (GC) is one of the most malignant tumors worldwide. Thus, it is necessary to explore the underlying mechanisms of GC progression and develop novel therapeutic regimens. Long non-coding RNAs (lncRNAs) have been demonstrated to be abnormally expressed and regulate the malignant behaviors of cancer cells. Our previous research demonstrated that lncRNA colon cancer-associated transcript 2 (CCAT2) has potential value for GC diagnosis and discrimination. However, the functional mechanisms of lncRNA CCAT2 in GC development remain to be explored. METHODS: GC and normal adjacent tissues were collected to detect the expression of lncRNA CCAT2, ESRP1 and CD44 in clinical specimens and their clinical significance for GC patients. Cell counting kit-8, wound healing and transwell assays were conducted to investigate the malignant behaviors in vitro. The generation of nude mouse xenografts by subcutaneous, intraperitoneal and tail vein injection was performed to examine GC growth and metastasis in vivo. Co-immunoprecipitation, RNA-binding protein pull-down assay and fluorescence in situ hybridization were performed to reveal the binding relationships between ESRP1 and CD44. RESULTS: In the present study, lncRNA CCAT2 was overexpressed in GC tissues compared to adjacent normal tissues and correlated with short survival time of patients. lncRNA CCAT2 promoted the proliferation, migration and invasion of GC cells. Its overexpression modulates alternative splicing of Cluster of differentiation 44 (CD44) variants and facilitates the conversion from the standard form to variable CD44 isoform 6 (CD44v6). Mechanistically, lncRNA CCAT2 upregulated CD44v6 expression by binding to epithelial splicing regulatory protein 1 (ESRP1), which subsequently mediates CD44 alternative splicing. The oncogenic role of the lncRNA CCAT2/ESRP1/CD44 axis in the promotion of malignant behaviors was verified by both in vivo and in vitro experiments. CONCLUSIONS: Our findings identified a novel mechanism by which lncRNA CCAT2, as a type of protein-binding RNA, regulates alternative splicing of CD44 and promotes GC progression. This axis may become an effective target for clinical diagnosis and treatment.

Removal and transformation of disinfection by-products in water during boiling treatment.

Disinfection by-products (DBPs) remain an ongoing issue because of their widespread occurrence and toxicity. Boiling is the most popular household water treatment method and can effectively remove some DBPs. However, the transformation behavior of DBPs during boiling is still unclear, and the key contributors to toxicity have not been identified. In this study, the changes in the concentrations of DBPs in the single-DBP systems and the multi-DBP systems during boiling were monitored, and in-depth discussions on the removal and transformation of DBPs in both systems were carried out. The results showed that boiling was effective in removing volatile DBPs (over 90% for TCAL, TCAN, and DCAN, and over 60% for TCM), but ineffective for non-volatile DBPs (around 20% for TCAA and below 10% for DCAA and MCAA). By hydrolysis and decarboxylation, the transformation occurred among DBPs, i.e., 55% TCAL to TCM, followed by 23% DCAN to DCAA, 22% TCAN to TCAA, and 10% TCAA to TCM. The transformations were found to be significantly influenced by other co-existing DBPs. In multi-DBP systems, the transformations of DCAN to DCAA and TCAN to TCAA were both promoted, while the transformation of TCAN to TCAA was inhibited. Transformation and volatilization are the two processes responsible for DBP removal. Toxicity estimates indicated that boiling was effective in reducing the toxicity of DBPs and improving the safety of the water, despite the interconversion of DBPs in drinking water during boiling. This study emphasized the importance of studying the interconversion behaviors of DBPs in drinking water during boiling and provided practical information for end-use drinking water safety.

Data adaptive regularization with reference tissue constraints for liver quantitative susceptibility mapping.

PURPOSE: To improve repeatability and reproducibility across acquisition parameters and reduce bias in quantitative susceptibility mapping (QSM) of the liver, through development of an optimized regularized reconstruction algorithm for abdominal QSM. METHODS: An optimized approach to estimation of magnetic susceptibility distribution is formulated as a constrained reconstruction problem that incorporates estimates of the input data reliability and anatomical priors available from chemical shift-encoded imaging. The proposed data-adaptive method was evaluated with respect to bias, repeatability, and reproducibility in a patient population with a wide range of liver iron concentration (LIC). The proposed method was compared to the previously proposed and validated approach in liver QSM for two multi-echo spoiled gradient-recalled echo protocols with different acquisition parameters at 3T. Linear regression was used for evaluation of QSM methods against a reference FDA-approved R 2 $$ {R}_2 $$ -based LIC measure and R 2 ∗ $$ {R}_2^{\ast } $$ measurements; repeatability/reproducibility were assessed by Bland-Altman analysis. RESULTS: The data-adaptive method produced susceptibility maps with higher subjective quality due to reduced shading artifacts. For both acquisition protocols, higher linear correlation with both R 2 $$ {R}_2 $$ - and R 2 ∗ $$ {R}_2^{\ast } $$ -based measurements were observed for the data-adaptive method ( r 2 = 0 . 74 / 0 . 69 $$ {r}^2=0.74/0.69 $$ for R 2 $$ {R}_2 $$ , 0 . 97 / 0 . 95 $$ 0.97/0.95 $$ for R 2 ∗ $$ {R}_2^{\ast } $$ ) than the standard method ( r 2 = 0 . 60 / 0 . 66 $$ {r}^2=0.60/0.66 $$ and 0 . 79 / 0 . 88 $$ 0.79/0.88 $$ ). For both protocols, the data-adaptive method enabled better test-retest repeatability (repeatability coefficients 0.19/0.30 ppm for the data-adaptive method, 0.38/0.47 ppm for the standard method) and reproducibility across protocols (reproducibility coefficient 0.28 vs. 0.53ppm) than the standard method. CONCLUSIONS: The proposed data-adaptive QSM algorithm may enable quantification of LIC with improved repeatability/reproducibility across different acquisition parameters as 3T.

Inhibition of androgen receptor enhanced the anticancer effects of everolimus through targeting glucose transporter 12.

Everolimus was designed as a mammalian target of rapamycin (mTOR) inhibitor. It has been proven as a targeted drug for gastric cancer (GC) therapy. However, long-term treatment with everolimus may cause severe side effects for recipients. Decreasing the dosage and attenuating the associated risks are feasible to promote clinical translation of everolimus. This study aimed to identify the underlying mechanisms of responses to everolimus and develop novel regimens for GC treatment. Our findings proved that there was a significant dose-dependent relationship of everolimus-induced GC cell apoptosis and glycolysis inhibition. Then, we found that a member of glucose transporter (GLUT12) family, GLUT12, was actively upregulated to counteract the anticancer effects of everolimus. GLUT12 might be overexpressed in GC. High expression of GLUT12 might be correlated with tumor progression and short survival time of GC patients. Bioinformatic analysis suggested that GLUT12 might be involved in regulating cancer development and metabolism. The experiments proved that GLUT12 significantly promoted GC growth, glycolysis and impaired the anticancer effects of everolimus. Androgen receptor (AR) is a classical oncogenic factor in many types of cancer. Everolimus elevated GLUT12 expression in an AR-dependent manner. Inhibition of AR activity abrogated the promotive effects on GLUT12 expression. Both in-vitro and in-vivo experiments demonstrated that GLUT12 knockdown augmented anticancer effects of everolimus. Enzalutamide, an AR inhibitor, or AR knockdown was comparable to GLUT12 suppression. This study identified the role of the AR/GLUT12 pathway in the development of poor responses to everolimus. Interference with AR/GLUT12 pathway may serve as a promising approach to promoting the translational application of everolimus in GC therapy.

Multicenter Reproducibility of Liver Iron Quantification with 1.5-T and 3.0-T MRI.

Background MRI is a standard of care tool to measure liver iron concentration (LIC). Compared with regulatory-approved R2 MRI, R2* MRI has superior speed and is available in most MRI scanners; however, the cross-vendor reproducibility of R2*-based LIC estimation remains unknown. Purpose To evaluate the reproducibility of LIC via single-breath-hold R2* MRI at both 1.5 T and 3.0 T with use of a multicenter, multivendor study. Materials and Methods Four academic medical centers using MRI scanners from three different vendors (three 1.5-T scanners, one 2.89-T scanner, and two 3.0-T scanners) participated in this prospective cross-sectional study. Participants with known or suspected liver iron overload were recruited to undergo multiecho gradient-echo MRI for R2* mapping at 1.5 T and 3.0 T (2.89 T or 3.0 T) on the same day. R2* maps were reconstructed from the multiecho images and analyzed at a single center. Reference LIC measurements were obtained with a commercial R2 MRI method performed using standardized 1.5-T spin-echo imaging. R2*-versus-LIC calibrations were generated across centers and field strengths using linear regression and compared using F tests. Receiver operating characteristic (ROC) curve analysis was used to determine the diagnostic performance of R2* MRI in the detection of clinically relevant LIC thresholds. Results A total of 207 participants (mean age, 38 years ± 20 [SD]; 117 male participants) were evaluated between March 2015 and September 2019. A linear relationship was confirmed between R2* and LIC. All calibrations within the same field strength were highly reproducible, showing no evidence of statistically significant center-specific differences (P > .43 across all comparisons). Calibrations for 1.5 T and 3.0 T were generated, as follows: for 1.5 T, LIC (in milligrams per gram [dry weight]) = -0.16 + 2.603 × 10-2 R2* (in seconds-1); for 2.89 T, LIC (in milligrams per gram) = -0.03 + 1.400 × 10-2 R2* (in seconds-1); for 3.0 T, LIC (in milligrams per gram) = -0.03 + 1.349 × 10-2 R2* (in seconds-1). Liver R2* had high diagnostic performance in the detection of clinically relevant LIC thresholds (area under the ROC curve, >0.98). Conclusion R2* MRI enabled accurate and reproducible quantification of liver iron overload over clinically relevant ranges of liver iron concentration (LIC). The data generated in this study provide the necessary calibrations for broad clinical dissemination of R2*-based LIC quantification. ClinicalTrials.gov registration no.: NCT02025543 © RSNA, 2022 Online supplemental material is available for this article.

Validation of liver quantitative susceptibility mapping across imaging parameters at 1.5 T and 3.0 T using SQUID susceptometry as reference.

PURPOSE: To validate QSM-based biomagnetic liver susceptometry (BLS) to measure liver iron overload at 1.5 T and 3.0 T using superconducting quantum interference devices (SQUID)-based BLS as reference. METHODS: Subjects with known or suspected iron overload were recruited for QSM-BLS at 1.5 T and 3.0 T using eight different protocols. SQUID-BLS was also obtained in each subject to provide susceptibility reference. A recent QSM method based on data-adaptive regularization was used to obtain susceptibility and R 2 * $$ {\mathrm{R}}_2^{\ast } $$ maps. Measurements of susceptibility and R 2 * $$ {\mathrm{R}}_2^{\ast } $$ were obtained in the right liver lobe. Linear mixed-effects analysis was used to estimate the contribution of specific acquisition parameters to QSM-BLS. Linear regression and Bland-Altman analyses were used to assess the relationship between QSM-BLS and SQUID-BLS/ R 2 * $$ {\mathrm{R}}_2^{\ast } $$ . RESULTS: Susceptibility maps showed high subjective quality for each acquisition protocol across different iron levels. High linear correlation was observed between QSM-BLS and SQUID-BLS at 1.5 T (r2 range, [0.82, 0.84]) and 3.0 T (r2 range, [0.77, 0.85]) across different acquisition protocols. QSM-BLS and R 2 * $$ {\mathrm{R}}_2^{\ast } $$ were highly correlated at both field strengths (r2 range at 1.5 T, [0.94, 0.99]; 3.0 T, [0.93, 0.99]). High correlation (r2  = 0.99) between 1.5 T and 3.0 T QSM-BLS, with narrow reproducibility coefficients (range, [0.13, 0.21] ppm) were observed for each protocol. CONCLUSION: This work evaluated the feasibility and performance of liver QSM-BLS across iron levels and acquisition protocols at 1.5 T and 3.0 T. High correlation and reproducibility were observed between QSM-BLS and SQUID-BLS across protocols and field strengths. In summary, QSM-BLS may enable reliable and reproducible quantification of liver iron concentration.

CdSe-Decorated Flowerlike CaMoO4 Microspheres with Enhanced Hydrogen Production Activity.

Photocatalytic hydrogen production technology from water is a more effective and promising method to solve energy and environmental crises. In this work, flowerlike CaMoO4 microspheres were successfully synthesized by an ultrasonic precipitation method and modified with variable concentrations of CdSe NCs. CdSe/CaMoO4 microspheres showed increased light absorption ability, larger relative surface area, lower electrochemical impedance, and longer fluorescence lifetime. The photocatalytic hydrogen production rate of CdSe/CaMoO4 microspheres could reach up to 10 162.33 µmol g-1 h-1. The constructed type-I heterostructure improved the separation of photogenerated electrons and inhibited the rapid recombination of photogenerated electrons and holes, thus enhancing the photocatalytic hydrogen production performance. CdSe/CaMoO4 with high hydrogen production activity would be an efficient photocatalyst for hydrogen production applications.

Comparison of short-term efficacy between totally laparoscopic gastrectomy and laparoscopic assisted gastrectomy for elderly patients with gastric cancer.

BACKGROUND: Totally laparoscopic gastrectomy (TLG) entails both gastrectomy and gastrointestinal reconstruction under laparoscopy. Compared with laparoscopic assisted gastrectomy (LAG), TLG has been demonstrated in many studies to require a smaller surgical incision, result in a faster postoperative recovery and less pain and have comparable long-term efficacy, which has been a research hotspot in recent years. Whether TLG is equally safe and feasible for elderly patients remains unclear. AIM: To compare the short-term efficacy of and quality of life (QOL) associated with TLG and LAG in elderly gastric cancer (GC) patients. METHODS: The clinicopathological data of 462 elderly patients aged ≥ 70 years who underwent LAG or TLG (including distal gastrectomy and total gastrectomy) between January 2017 and January 2022 at the Department of General Surgery, First Medical Center, Chinese PLA General Hospital were retrospectively collected. A total of 232 patients were in the LAG group, and 230 patients were in the TLG group. Basic patient information, clinicopathological characteristics, operation information and QOL data were collected to compare efficacy. RESULTS: Compared with those in the LAG group, intraoperative blood loss in the TLG group was significantly lower (P < 0.001), and the time to first flatus and postoperative hospitalization time were significantly shorter (both P < 0.001). The overall incidence of postoperative complications in the TLG group was significantly lower than that in the LAG group (P = 0.01). Binary logistic regression results indicated that LAG and an operation time > 220 min were independent risk factors for postoperative complications in elderly patients with GC (P < 0.05). In terms of QOL, no statistically significant differences in various preoperative indicators were found between the LAG group and the LTG group (P > 0.05). Compared with the laparoscopic-assisted total gastrectomy group, patients who received totally laparoscopic total gastrectomy had lower nausea and vomiting scores and higher satisfaction with their body image (P < 0.05). Patients who underwent laparoscopic-assisted distal gastrectomy were more satisfied with their body image than patients in the totally laparoscopic distal gastrectomy group (P < 0.05). CONCLUSION: TLG is safe and feasible for elderly patients with GC and has outstanding advantages such as reducing intracorporeal blood loss, promoting postoperative recovery and improving QOL.

Acute ammonia stress-induced oxidative and heat shock responses modulated by transcription factors in Litopenaeus vannamei.

The present study aimed to examine the effects of short-term exposure to ammonia on stress and oxidative responses in shrimp (Litopenaeus vannamei) and to determine whether the antioxidant system related to the regulatory role of transcription factors and stress proteins was activated. Shrimp were exposed ammonia-N at four concentrations: 0 (control), 5, 10, and 15 mg/L, for 48 h. The hepatopancreas was sampled to measure the levels of glutathione (GSH), malondialdehyde (MDA), nitric oxide (NO); the activities of superoxide dismutase (SOD), catalase (CAT), nitric oxide synthase (NOS); and the expression levels of GSH-px (encoding glutathione peroxidase), GST (encoding glutathione-S-transferase), HSP70 (encoding heat shock protein 70), HSP90 (encoding heat shock protein 90), p53, RELISH, and AKIRIN. We observed that exposure to a high ammonia content increased the abundance of oxidative factors (MDA, CAT, SOD, NOS, and NO), reduced the levels of GSH, and upregulated the mRNA expression levels of antioxidant genes (GSH-px and GST), stress-related genes (HSP70 and HSP90), and transcription factor genes (p53, RELISH, and AKIRIN). These results indicated that ammonia induced oxidative stress and inflammation. Both enzymatic and nonenzymatic antioxidant defense systems are involved, which might be regulated by HSPs, as well as certain transcription factors, such as p53 and nuclear factor kappa B (NF-κB), thus mounting an adaptive response to help rebalance redox homoeostasis.

Oral administration of asparagine and 3-indolepropionic acid prolongs survival time of rats with traumatic colon injury.

BACKGROUND: Traumatic colon injury (TCI) is a common disease during wartime. Prolongation of posttraumatic survival time is an effective approach to patient outcome improvement. However, there is a lack of basic research in this field. This study aimed to elucidate the mechanisms underlying TCI progression and to develop novel regimens to buy time for TCI patients on the battlefield. METHODS: A total of 669 Sprague-Dawley rats were used in this study. Surgical colon incision was performed to generate the TCI rat model. The landscape of colon microbiota compositions was depicted using 16S rRNA sequencing and metabolites in the intestinal contents were detected by metabolomics profiling. The signaling transduction in the intestinal epithelium was investigated using antibody microarrays and Western blotting. The enzyme-linked immunosorbent assay was conducted to measure the levels of interleukin-6 and tumor necrosis factor-α in intestines and plasma for the detection of inflammatory responses. Diamine oxidase, D-lactate and endotoxin in plasma and protein expression of zonula occludens 1 and occludin were selected as the indicators of intestinal barrier permeability. To investigate alterations of microbiota symbiosis, the relative abundances of specific bacterial genera were detected using quantitative real-time PCR. RESULTS: As a type of lethal injury, TCI induced acute disruption of intestinal homeostasis, characterized by inflammatory responses, intestinal barrier hyperpermeability and microbiota dysbiosis (P < 0.05). Significant alterations in bacterial metabolic patterns were detected with decreases in many metabolites. After a series of screenings, we found that oral administration of asparagine (Asn) and 3-indolepropionic acid (IPA) effectively prolonged posttraumatic survival time [Asn plus IPA vs. Vehicle: hazard ratio (HR) = 0.105, 95% CI 0.031-0.356, P = 0.0003] and restored intestinal homeostasis in TCI rats (P < 0.05). Mechanistically, this combinational strategy protected the rats against TCI through synergistic activation of Akt signaling in the intestinal epithelium (P < 0.05). CONCLUSIONS: Abrupt dysregulation of intestinal homeostasis plays a critical role in the progression toward TCI-induced death. Oral administration of Asn plus IPA may serve as an effective regimen to restore intestinal functions and prolong the posttraumatic survival time.

Short and long-term outcomes between laparoscopic and open total gastrectomy for advanced gastric cancer after neoadjuvant chemotherapy.

BACKGROUND: Neoadjuvant chemotherapy (NACT) combined with surgery is regarded as an effective treatment for advanced gastric cancer (AGC). Laparoscopic surgery represents the mainstream of minimally invasive surgery. Currently, surgeons focus more on surgical safety and oncological outcomes of laparoscopic gastrectomy after NACT. Thus, we sought to evaluate short- and long-term outcomes between laparoscopic total gastrectomy (LTG) and open total gastrectomy (OTG) after NACT. AIM: To compare the short and long-term outcomes between LTG and OTG for AGC after NACT. METHODS: We retrospectively collected the clinicopathological data of 136 patients who accepted gastrectomy after NACT from June 2012 to June 2019, including 61 patients who underwent LTG and 75 who underwent OTG. Clinicopathological characteristics between the LTG and OTG groups showed no significant difference. SPSS 26.0, R software, and GraphPad PRISM 8.0 were used to perform statistical analyses. RESULTS: Of the 136 patients included, eight acquired pathological complete response, and the objective response rate was 47.8% (65/136). The LTG group had longer operation time (P = 0.015), less blood loss (P = 0.003), shorter days to first flatus (P < 0.001), and shorter postoperative hospitalization days (P < 0.001). LTG spent more surgical cost than OTG (P < 0.001), while total hospitalized cost of LTG was less than OTG (P < 0.001). 21 (28.0%) patients in the OTG group and 14 (23.0%) in the LTG group had 30-d postoperative complications, but there was no significant difference between the two groups (P = 0.503). The 3-year overall survival (OS) rate was 60.6% and 64.6% in the LTG and OTG groups, respectively [hazard ratio (HR) = 0.859, 95% confidence interval (CI): 0.522-1.412, P = 0.546], while the 3-year disease-free survival (DFS) rate was 54.5% and 51.8% in the LTG and OTG group, respectively (HR = 0.947, 95%CI: 0.582-1.539, P = 0.823). Multivariate cox analysis showed that body mass index and pTNM stage were independent risk factors for OS while vascular invasion and pTNM stage were independent risk factors for DFS (P < 0.05). CONCLUSION: After NACT, LTG shows comparable 30-d postoperative morbidity as well as 3-year OS and DFS rate to OTG. We recommend that experienced surgeons select LTG other than OTG for proper AGC patients after NACT.

The Significance of Neutrophil Extracellular Traps in Colorectal Cancer and Beyond: From Bench to Bedside.

Neutrophil extracellular traps (NETs), products of neutrophil death when exposed to certain stimuli, were first proposed as a type of response to bacterial infection in infectious diseases. Since then, extensive studies have discovered its involvement in other non-infectious inflammatory diseases including thromboembolism, autoimmune diseases, and cancer. Colorectal cancer (CRC) is one of the most common malignancies in the world. NET formation is closely associated with tumorigenesis, progression, and metastasis in CRC. Therefore, the application of NETs in clinical practice as diagnostic biomarkers, therapeutic targets, and prognostic predictors has a promising prospect. In addition, therapeutics targeting NETs are significantly efficient in halting tumor progression in preclinical cancer models, which further indicates its potential clinical utility in cancer treatment. This review focuses on the stimuli of NETosis, its pro-tumorigenic activity, and prospective clinical utility primarily in but not limited to CRC.

circDNMT1 Promotes Malignant Progression of Gastric Cancer Through Targeting miR-576-3p/Hypoxia Inducible Factor-1 Alpha Axis.

Background: Circular RNAs (circRNAs) regulate multiple malignant behaviors of various types of cancer. The role of circDNMT1, a newly identified circRNA, remains unknown in gastric cancer (GC). This study aimed to elucidate the underlying mechanisms of circDNMT1 in regulating GC progression. Methods: microRNA (miRNA) and circRNA expression was detected by quantitative real-time PCR. Western blotting was performed to measure hypoxia inducible factor-1 alpha (HIF-1α) protein expression. Sanger sequencing, gel electrophoresis and fluorescence in situ hybridization were performed to identify the presence of circDNMT1. The clinicopathological features and overall survival of patients were analyzed based on circDNMT1 expression. The proliferation, migration and invasion of GC cells were determined by cell counting kit-8, 5-ethynyl-2'-deoxyuridine, wound healing and transwell assays. Glycolysis of GC cells was detected based on the levels of glucose uptake, the lactate acid, ATP and pyruvic acid production and the extracellular acidification and oxygen consumption rates. The binding sites between miR-576-3p and circDNMT1 or HIF-1α were predicted by online bioinformatic tools and were validated using RNA pull-down and luciferase reporter assays. Xenograft models were established to determine the effects of the circDNMT1/miR-576-3p/HIF-1α axis on GC growth and metastasis in vivo. Results: circDNMT1 was successfully identified and shown to be overexpressed in GC tissues and cell lines. The expression levels of circDNMT1 were correlated with pathological T stage, pathological TNM stage and shorter survival time of GC patients. circDNMT1 knockdown inhibited the proliferation, migration, invasion and glycolysis of GC cells. circDNMT1 functioned as an oncogenic factor by sponging miR-576-3p. HIF-1α was negatively regulated by miR-576-3p via binding its mRNA 3' untranslated region. circDNMT1 promoted malignant behaviors and metabolic reprogramming of GC by targeting the miR-576-3p/HIF-1α axis both in vitro and in vivo. Conclusion: These findings demonstrated that circDNMT1 knockdown inhibited GC proliferation, migration, invasion and glycolysis through sponging miR-576-3p/HIF-1α axis. circDNMT1 may be a novel target for GC treatment.