Added value of histogram analysis of intravoxel incoherent motion and diffusion kurtosis imaging for the evaluation of complete response to neoadjuvant therapy in locally advanced rectal cancer.

OBJECTIVE: To evaluate how intravoxel incoherent motion (IVIM) and diffusion kurtosis imaging (DKI) histogram analysis contribute to assessing complete response (CR) to neoadjuvant therapy (NAT) in locally advanced rectal cancer (LARC). MATERIAL AND METHODS: In this prospective study, participants with LARC, who underwent NAT and subsequent surgery, with adequate MR image quality, were enrolled from November 2021 to March 2023. Conventional MRI (T2WI and DWI), IVIM, and DKI were performed before NAT (pre-NAT) and within two weeks before surgery (post-NAT). Image evaluation was independently performed by two experienced radiologists. Pathological complete response (pCR) was used as the reference standard. An IVIM-DKI-added model (a combination of IVIM and DKI histogram parameters with T2WI and DWI) was constructed. Receiver operating characteristic (ROC) curves were generated to evaluate the diagnostic performance of conventional MRI and the IVIM-DKI-added model. RESULTS: A total of 59 participants (median age: 58.00 years [IQR: 52.00, 62.00]; 38 [64%] men) were evaluated, including 21 pCR and 38 non-pCR cases. The histogram parameters of DKI, including skewness of kurtosis post-NAT (post-KSkewness) and root mean squared of change ratio of diffusivity (Δ%DDKI-root mean squared), were entered into the IVIM-DKI-added model. The area under the ROC curve (AUC) of the IVIM-DKI-added model for assessing CR to NAT was significantly higher than that of conventional MRI (0.855 [95% CI: 0.749-0.960] vs 0.685 [95% CI: 0.565-0.806], p < 0.001). CONCLUSION: IVIM and DKI provide added value in the evaluation of CR to NAT in LARC. KEY POINTS: Question The current conventional imaging evaluation system lacks adequacy for assessing CR to NAT in LARC. Findings Significantly improved diagnostic performance was observed with the histogram analysis of IVIM and DKI in conjunction with conventional MRI. Clinical relevance IVIM and DKI provide significant value in evaluating CR to NAT in LARC, which bears significant implications for reducing surgical complications and facilitating organ preservation.

HER2 becomes a novel survival biomarker for gastric cancer patients: a pooled analysis.

Background: Although anti-HER2 therapies have been widely used against gastric carcinoma, the prognostic significance of HER2 overexpression remains unclear. Previous studies failed to provide convincible evidence due to inconsistent HER2 evaluation criteria and heterogeneous clinical characteristics. Objectives: To figure out the prognostic significance of HER2 expression in gastric cancer, we rigorously designed and conducted this study. Design: Meta-analysis. Data sources and methods: Record retrieval was performed by searching PubMed, Web of Science, Cochrane Library, Embase, ASCO, and ESMO meeting libraries from inception to November 2022. Cohort studies investigating overall survival comparison between HER2-positive and HER2-negative gastric cancer patients were included. Both resectable and advanced cases were separately collected while HER2 evaluation standards should be consistent across eligible studies. Newcastle-Ottawa Scale was used for quality assessment. Overall survival was the only endpoint and effect size was presented by hazard ratio (HR) with its 95% confidence interval. The pooled calculation was conducted on Review Manager 5.4. Results: Thirty studies were eligible, including 9945 patients. Eligible studies were mostly high quality (n = 31). Regarding resectable cases (n = 22), HER2-positive groups had significantly worse prognosis than HER2-negative counterparts (HR 1.56, 95%CI 1.32-1.85, p < 0.00001). For HER2-positive patients with advanced gastric cancer (n = 10), HER2 overexpression was also an unfavorable survival indicator (HR 1.70, 95%CI 1.23-2.35, p = 0.001). Potential heterogeneous studies had been eliminated while outcomes remained stable by sensitivity analysis. Subgroup analysis suggested HER2-positive patients had a poorer prognosis in both East Asian (resectable: HR 1.56; advanced: HR 1.32) and non-East Asian countries (HR 1.58; HR 3.27). Conclusion: As a novel survival biomarker in gastric cancer, HER2 overexpression indicates unfavorable prognosis among both resectable and advanced patients, irrespective of East Asian or non-East Asian populations. Trial registration: PROSPERO (CRD42020168051).

Neural Circuitries between the Brain and Peripheral Solid Tumors.

The recent discovery of the pivotal role of central nervous system (CNS) in controlling tumor initiation and progression has opened a new field of research. Increasing evidence suggests a bidirectional interaction between the brain and tumors. The brain influences the biological behavior of tumor cells through complex neural networks involving the peripheral nervous system, the endocrine system, and the immune system, while tumors can establish local autonomic and sensory neural networks to transmit signals into the CNS, thereby affecting brain activity. This review aims to summarize the latest research in brain-tumor crosstalk, exploring neural circuitries between the brain and various peripheral solid tumors, analyzing the roles in tumor development and the related molecular mediators and pathological mechanisms, and highlighting the critical impact on the understanding of cancer biology. Enhanced understanding of reciprocal communication between the brain and tumors will establish a solid theoretical basis for further research and could open avenues for repurposing psychiatric interventions in cancer treatment.

GATIS score for predicting the prognosis of rectal neuroendocrine neoplasms: A Chinese multicenter study of 12-year experience.

BACKGROUND: There is currently a shortage of accurate, efficient, and precise predictive instruments for rectal neuroendocrine neoplasms (NENs). AIM: To develop a predictive model for individuals with rectal NENs (R-NENs) using data from a large cohort. METHODS: Data from patients with primary R-NENs were retrospectively collected from 17 large-scale referral medical centers in China. Random forest and Cox proportional hazard models were used to identify the risk factors for overall survival and progression-free survival, and two nomograms were constructed. RESULTS: A total of 1408 patients with R-NENs were included. Tumor grade, T stage, tumor size, age, and a prognostic nutritional index were important risk factors for prognosis. The GATIS score was calculated based on these five indicators. For overall survival prediction, the respective C-indexes in the training set were 0.915 (95% confidence interval: 0.866-0.964) for overall survival prediction and 0.908 (95% confidence interval: 0.872-0.944) for progression-free survival prediction. According to decision curve analysis, net benefit of the GATIS score was higher than that of a single factor. The time-dependent area under the receiver operating characteristic curve showed that the predictive power of the GATIS score was higher than that of the TNM stage and pathological grade at all time periods. CONCLUSION: The GATIS score had a good predictive effect on the prognosis of patients with R-NENs, with efficacy superior to that of the World Health Organization grade and TNM stage.

Laparoscopic versus open surgery for rectal neuroendocrine tumors: a multicenter real-world study.

BACKGROUND: Owing to the lack of evidence-based medical studies with large sample sizes, the surgical approach for the radical resection of rectal neuroendocrine tumors remains controversial. METHODS: We retrospectively collected the medical records of patients with rectal neuroendocrine tumors who underwent radical resection at 17 large tertiary care hospitals in China between January 1, 2010, and April 30, 2022. All patients were divided into laparoscopic and open surgery groups. After propensity score matching to reduce confounders, the postoperative and oncologic outcomes were compared between the groups. RESULTS: We enrolled 174 patients with rectal neuroendocrine tumors who underwent radical surgery. After random matching, 124 patients were included in the comparison (62, laparoscopic surgery group; 62, open surgery group). The laparoscopic surgery group had fewer complications (14.5% vs. 35.5%, P = 0.007) and superior relapse-free survival (P = 0.048). Subgroup analysis revealed that the laparoscopic surgery group had fewer complications (10.9% vs. 34.7%, P = 0.004), shorter postoperative hospital stays (9.56 ± 5.21 days vs. 12.31 ± 8.61 days, P = 0.049) and superior relapse-free survival (P = 0.025) in the rectal neuroendocrine tumors ≤ 4 cm subgroup. CONCLUSIONS: Laparoscopic surgery was associated with improved postoperative outcomes and oncologic prognosis for patients with rectal neuroendocrine tumors ≤ 4 cm; it can serve as a safe and feasible option for radical surgery of rectal neuroendocrine tumors.

Two-Year Outcomes and Biomarker Analysis of Locally Advanced Gastric and Gastroesophageal Junction Adenocarcinoma After Neoadjuvant Chemotherapy and Immunotherapy from the Phase II WuhanUHGI001 Trial.

BACKGROUND: This study reports the 2-year outcomes and biomarker analysis results of patients with locally advanced gastric and gastroesophageal junction (G/GEJ) adenocarcinoma who received neoadjuvant chemotherapy and immunotherapy in a phase II WuhanUHGI001 trial. METHODS: Eligible patients with cT3/4aN+M0 locally advanced G/GEJ adenocarcinoma were screened, enrolled, and treated with 3 cycles of neoadjuvant tislelizumab and SOX followed by D2 gastrectomy and another 5 cycles of postoperative adjuvant SOX. The primary endpoint was major pathological response. RESULTS: Of the 49 included patients, 24 (49.0%) achieved major pathological response and 13 (26.5%) achieved pathological complete response. During a median follow-up of 26.8 months, the 2-year progression-free survival (PFS) and overall survival (OS) rates were 69.4% and 81.2%, respectively. Grade 3-4 adverse events occurred in six patients (12.2%) during the neoadjuvant period, eight patients (17.0%) during the postoperative period, and seven patients (15.2%) during the adjuvant period. Biomarker analysis revealed that the pathological complete response showed no association with 2-year PFS and OS. Major pathological response showed a potentially strong association with improved 2-year PFS and OS rates. In addition, preoperative circulating tumor cells combined with pathological responses are helpful in prognosis assessment. In addition, our results showed that T downstaging, lymphocyte-to-monocyte ratio, and CD3+ T cells were independent factors that affect PFS. The signet ring cell component (SRCC), T downstaging, and neutrophil-to-lymphocyte ratio were independent factors affecting OS. Prognostic nomograms of PFS and OS constructed based on the multivariate Cox regression results demonstrated suitable calibration and discrimination ability. CONCLUSIONS: Neoadjuvant tislelizumab plus SOX exhibits promising efficacy and acceptable toxicity in patients with locally advanced G/GEJ adenocarcinoma. In addition, our study established a prognostic risk signature and nomograms based on clinicopathological characteristics, which can accurately predict patient outcomes and aid in personalized treatment planning.

Intratumoral microbiome promotes liver metastasis and dampens adjuvant imatinib treatment in gastrointestinal stromal tumor.

Understanding the determinants of long-term liver metastasis (LM) outcomes in gastrointestinal stromal tumor (GIST) patients is crucial. We established the feature selection model of intratumoral microbiome at the surgery, achieving robust predictive accuracies of 0.953 and 0.897 AUCs in discovery (n = 74) and validation (n = 34) cohorts, respectively. Notably, despite the significant reduction in LM occurrence with adjuvant imatinib (AI) treatment, intratumoral microbiome exerted independently stronger effects on post-operative LM. Employing both 16S and full-length rRNA sequencing, we pinpoint intracellular Shewanella algae as a foremost LM risk factor in both AI- and non-AI-treated patients. Experimental validation confirmed S. algae's intratumoral presence in GIST, along with migration/invasion-promoting effects on GIST cells. Furthermore, S. algae promoted LM and impeded AI treatment in metastatic mouse models. Our findings advocate for incorporating intratumoral microbiome evaluation at surgery, and propose S. algae as a therapeutic target for LM suppression in GIST.

Analysis of clinicopathological characteristics and prognosis on primary gastric adenosquamous carcinoma.

Primary gastric adenosquamous carcinoma (PGASC) is a rare type of gastric cancer with limited research and poorly understood clinicopathological features. This study investigated the clinicopathological features and outcomes of PGASC. Patients with PGASC from Union Hospital, Tongji Medical College, Huazhong University of Science and Technology and from the published literature were enrolled in this study. Survival curves were generated using the Kaplan-Meier method, and prognostic factors were identified through Cox proportional hazards regression models. This study identified 76 eligible cases of PGASC, with 45 cases from published literature and 31 from our center. The most prevalent symptoms were abdominal pain and dysphagia, with a median age of 62 years (range: 29-84 years). The primary lesions were predominantly in the proximal stomach, with a median tumor size of 6.5 cm (range: 1.5-16.0 cm). Tumor stages II, III, and IV were detected in 12 (16.7%), 43 (59.7%), and 17 (23.6%) patients, respectively. Most tumors were poorly differentiated in both the squamous cell carcinoma (SCC) component and adenocarcinoma (AC) component. The median survival time was 17 months (range: 2-122 months). The 1, 3, and 5-year overall survival (OS) was 60.7%, 31.1%, and 24.1%, respectively. Multivariate analysis revealed that OS was independently predicted by the proportion of SCC component, differentiation of AC component, and tumor stage. PGASC is a rare disease with a poor prognosis. A high proportion of SCC components, low differentiated AC components, and advanced tumor were associated with worse survival in patients with PGASC. Adjuvant therapy did not improve survival time.

Inhibition of glycolysis enhances the efficacy of immunotherapy via PDK-mediated upregulation of PD-L1.

BACKGROUND: Immunotherapy for gastric cancer remains a challenge due to its limited efficacy. Metabolic reprogramming toward glycolysis has emerged as a promising avenue for enhancing the sensitivity of tumors to immunotherapy. Pyruvate dehydrogenase kinases (PDKs) play pivotal roles in regulating glycolysis. The importance of PDKs in the context of gastric cancer immunotherapy and their potential as therapeutic targets have not been fully explored. METHODS: PDK and PD-L1 expression was analyzed using data from the GSE66229 and The Cancer Genome Atlas (TCGA) cohorts. Additionally, the Immune Checkpoint Blockade Therapy Atlas (ICBatlas) database was utilized to assess PDK expression in an immune checkpoint blockade (ICB) therapy group. Subsequently, the upregulation of PD-L1 and the enhancement of anticancer effects achieved by targeting PDK were validated through in vivo and in vitro assays. The impact of PDK on histone acetylation was investigated using ChIP‒qPCR to detect changes in histone acetylation levels. RESULTS: Our analysis revealed a notable negative correlation between PD-L1 and PDK expression. Downregulation of PDK led to a significant increase in PD-L1 expression. PDK inhibition increased histone acetylation levels by promoting acetyl-CoA generation. The augmentation of acetyl-CoA production and concurrent inhibition of histone deacetylation were found to upregulate PD-L1 expression in gastric cancer cells. Additionally, we observed a significant increase in the anticancer effect of PD-L1 antibodies following treatment with a PDK inhibitor. CONCLUSIONS: Downregulation of PDK in gastric cancer cells leads to an increase in PD-L1 expression levels, thus potentially improving the efficacy of PD-L1 immune checkpoint blockade therapy.

Laparoscopic Sigmoid Vaginoplasty for the Treatment of Mayer-Rokitansky-Kuster-Hauser Syndrome in a Single Center: 20 years' Experience.

INTRODUCTION AND HYPOTHESIS: We investigate the feasibility, safety, and clinical therapeutic effect of laparoscopic sigmoid vaginoplasty in women with Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome. METHODS: We performed a retrospective case review cohort study of 56 patients with MRKHs undergoing laparoscopic sigmoid vaginoplasty in Wuhan Union Hospital between 2000 and 2020, and all patients were followed up. RESULTS: The median operating time was 165 min (120-420 min). The median hospital stay was 10 days (rang 7-15 days). A functional neovagina was created 11-15 cm in length and two fingers in breadth in all patients. No introitus stenosis was observed. No intra- or post-operative complications occurred. Two patients were lost to follow-up after 3 months of outpatient visits. Six patients had no intercourse and were required to wear a vaginal mold occasionally. None of the patients had complained of local irritation or dyspareunia. Patients who had post-surgery sexual intercourse were satisfied with their sexual life and the mean total Female Sexual Function Index (FSFI) score was 25.17 ± 0.63. The cosmetic results were excellent. CONCLUSIONS: The laparoscopic sigmoid vaginoplasty can achieve the goal of making a functional neovagina. The main advantage of this surgical technique is that it is minimally invasive and that there are fewer complications post-operation. It is an acceptable procedure for patients with MRKH syndrome.

Human gastric cancer progression and stabilization of ATG2B through RNF5 binding facilitated by autophagy-associated CircDHX8.

The role of circDHX8 in the interplay between autophagy and gastric cancer (GC) progression remains unclear. In this study, we investigated the mechanism underlying the role of hsa_circ_003899 (circDHX8) in the malignancy of GC. Differential expression of circRNAs between GC and normal tissues was determined using circle-seq and microarray datasets (GSE83521). These circRNAs were validated using qPCR and Sanger sequencing. The function of circDHX8 was investigated through interference with circDHX8 expression experiments using in vitro and in vivo functional assays. Western blotting, immunofluorescence, and transmission electron microscopy were used to establish whether circDHX8 promoted autophagy in GC cells. To elucidate the mechanism underlying the circDHX8-mediated regulation of autophagy, we performed bioinformatics analysis, RNA pull-down, mass spectrometry (MS), RNA immunoprecipitation (RIP), and other western Blot related experiments. Hsa_circ_0003899 (circDHX8) was identified as upregulated and shown to enhance the malignant progression in GC cells by promoting cellular autophagy. Mechanistically, circDHX8 increased ATG2B protein levels by preventing ubiquitin-mediated degradation, thereby facilitating cell proliferation and invasion in GC. Additionally, circDHX8 directly interacts with the E3 ubiquitin-protein ligase RNF5, inhibiting the RNF5-mediated degradation of ATG2B. Concurrently, ATG2B, an acetylated protein, is subjected to SIRT1-mediated deacetylation, enhancing its binding to RNF5. Consequently, we established a novel mechanism for the role of circDHX8 in the malignant progression of GC.

IRG1/itaconate alleviates acute liver injury in septic mice by suppressing NLRP3 expression and its mediated macrophage pyroptosis via regulation of the Nrf2 pathway.

Sepsis, a systemic inflammatory response triggered by infection, has a considerably high mortality rate. However, effective prevention and intervention measures against sepsis remain insufficient. Therefore, this study aimed to investigate the mechanisms underlying the protective properties of immune response gene-1 (IRG1) and 4-Octyl itaconate (OI) during acute liver damage in mice with sepsis. A sepsis mouse model was established to compare wild-type and IRG1-/- groups. The impact of IRG1/Itaconate on pro- and anti-inflammatory cytokines was evaluated using J774A.1 cells. IRG1/Itaconate substantially reduced pro-inflammatory cytokines and increased the release of anti-inflammatory cytokines. It reduced pathological damage to liver tissues, preserved normal liver function, decreased the release of reactive oxygen species (ROS) and LDH, and enhanced the GSH/GSSG ratio. Moreover, IRG1 and itaconic acid activated the Nrf2 signaling pathway, regulating the expression of its downstream antioxidative stress-related proteins. Additionally, they inhibited the activity of NLRP3 inflammatory vesicles to suppress the expression of macrophage-associated pyroptosis signaling molecules. Our findings demonstrate that IRG1/OI inhibits NLRP3 inflammatory vesicle activation and macrophage pyroptosis by modulating the Nrf2 signaling pathway, thereby attenuating acute liver injury in mice with sepsis. These findings could facilitate the clinical application of IRG1/Itaconate to prevent sepsis-induced acute liver injury.

Long-term outcomes of 1-2 cm rectal neuroendocrine tumors after local excision or radical resection: A population-based multicenter study.

Objectives: Studies on rectal neuroendocrine tumors (R-NETs) that are 1-2 cm in size are limited, and the optimal treatment for these tumors is not well established. Methods: Data from patients with primary localized R-NETs 1-2 cm in size were retrospectively collected from 17 large-scale referral medical centers in China. Long-term prognosis, quality of life (QOL), and fecal incontinence were evaluated, and the effects of local excision (LE) or radical resection (RR) were elucidated using propensity score matching (PSM). Results: A total of 272 patients were included in this study; 233 underwent LE, and the remaining 39 underwent RR. Patients in the LE group showed lower tumor location, fewer postoperative Clavien-Dindo III-V complications, more G1 tumors, and lower tumor stage. There were no significant differences in the relapse-free survival or overall survival (OS) between the LE and RR groups after PSM. Patients in the LE group reported superior physical, role, emotional, social, and cognitive functions, global QOL, and Wexner fecal incontinence scores compared with those in the RR group (all P < 0.050). Eighteen (6.6%) patients had lymph node metastases. Multivariable analysis revealed that tumor location (odds ratio [OR] = 3.19, 95% confidence interval [CI] 1.04-10.07, P = 0.010), neutrophil-to-lymphocyte ratio (NLR) > 1.80 (OR = 4.50, 1.46-15.89, P = 0.012), and T3-T4 (OR = 36.31, 95% CI 7.85-208.62, P < 0.001) were independent risk factor for lymph node metastasis. Conclusions: R-NETs measuring 1-2 cm generally have a favorable prognosis, and there is no difference in postoperative survival between LE and RR. For patients without lymph node metastasis, LE should be the preferred choice; however, for patients with a higher tumor location, preoperative NLR >1.8 or T3/T4 tumors, RR should be considered.

Neoadjuvant Chemotherapy With Oxaliplatin and Fluoropyrimidine Versus Upfront Surgery for Locally Advanced Colon Cancer: The Randomized, Phase III OPTICAL Trial.

PURPOSE: The role of neoadjuvant chemotherapy (NAC) in colon cancer remains unclear. This trial investigated whether 3 months of modified infusional fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or capecitabine and oxaliplatin (CAPOX) as NAC could improve outcomes in patients with locally advanced colon cancer versus upfront surgery. PATIENTS AND METHODS: OPTICAL was a randomized, phase III trial in patients with clinically staged locally advanced colon cancer (T3 with extramural spread into the mesocolic fat ≥5 mm or T4). Patients were randomly assigned 1:1 to receive six preoperative cycles of mFOLFOX6 or four cycles of CAPOX, followed by surgery and adjuvant chemotherapy (NAC group), or immediate surgery and the physician's choice of adjuvant chemotherapy (upfront surgery group). The primary end point was 3-year disease-free survival (DFS) assessed in the modified intention-to-treat (mITT) population. RESULTS: Between January 2016 and April 2021, of the 752 patients enrolled, 744 patients were included in the mITT analysis (371 in the NAC group; 373 in the upfront surgery group). At a median follow-up of 48.0 months (IQR, 46.0-50.1), 3-year DFS rates were 82.1% in the NAC group and 77.5% in the upfront surgery group (stratified hazard ratio [HR], 0.74 [95% CI, 0.54 to 1.03]). The R0 resection was achieved in 98% of patients who underwent surgery in both groups. Compared with upfront surgery, NAC resulted in a 7% pathologic complete response rate (pCR), significantly lower rates of advanced tumor staging (pT3-4: 77% v 94%), lymph node metastasis (pN1-2: 31% v 46%), and potentially improved overall survival (stratified HR, 0.44 [95% CI, 0.25 to 0.77]). CONCLUSION: NAC with mFOLFOX6 or CAPOX did not show a significant DFS benefit. However, this neoadjuvant approach was safe, resulted in substantial pathologic downstaging, and appears to be a viable therapeutic option for locally advanced colon cancer.

The circMYBL2-Encoded p185 Protein Suppresses Colorectal Cancer Progression by Inhibiting Serine Biosynthesis.

Circular RNAs are a class of covalently closed single-stranded loop RNAs that have been implicated to play a functional role in almost all types of cancers. Previous studies have revealed that circMYBL2 acts as a tumor-promoting circular RNA. In this study, we found that circMYBL2 in colorectal cancer encodes a 185-amino acid protein, p185. Functionally, circMYBL2-encoded p185 suppressed the growth and aggressiveness of colorectal cancer cells in vitro and in vivo. Mechanistically, p185 counteracted ubiquitin C-terminal hydrolase L3 (UCHL3)-mediated deubiquitination of phosphoglycerate dehydrogenase (PHGDH) by competitively binding to the C1 domain of UCHL3, resulting in PHGDH degradation and a subsequent reduction in serine and glycine biosynthesis. These data revealed that the circMYBL2-encoded p185 isoform serves as a tumor suppressor to inhibit the progression of colorectal cancer by reducing serine biosynthesis. Significance: A p185 protein encoded by circMYBL2 functions as a tumor suppressor that inhibits the progression of colorectal cancer by increasing the degradation of PHGDH to reduce serine biosynthesis.

IRG1/Itaconate inhibits proliferation and promotes apoptosis of CD69+CD103+CD8+ tissue-resident memory T cells in autoimmune hepatitis by regulating the JAK3/STAT3/P53 signalling pathway.

To investigate the protective role of immune response gene 1 (IRG1) and exogenous itaconate in autoimmune hepatitis (AIH) and elucidate the underlying mechanisms. Wild-type and IRG1-/- AIH mouse models were established, and samples of liver tissue and ocular blood were collected from each group of mice to assess the effects of IRG1/itaconate on the expression of pro- and anti-inflammatory cytokines. The levels of liver enzymes and related inflammatory factors were determined using enzyme-linked immunosorbent assay and real-time quantitative polymerase chain reaction (PCR). Liver histomorphology was detected through hematoxylin and eosin staining and then scored for liver injury, and the infiltration levels of tissue-resident memory T (TRM) cells and related molecules in the liver tissue were detected through immunofluorescence staining in vitro. RNA sequencing and gene enrichment analysis were conducted to identify the corresponding molecules and pathways, and lentiviral transfection was used to generate TRM cell lines with IRG1, Jak3, Stat3, and p53 knockdown. Real-time quantitative PCR and western blot were performed to detect the expression levels of relevant mRNAs and proteins in the liver tissue and cells. The percentage of apoptotic cells was determined using flow cytometry. IRG1/itaconate effectively reduced the release of pro-inflammatory cytokines and the pathological damage to liver tissue, thereby maintaining normal liver function. At the same time, IRG1/itaconate inhibited the JAK3/STAT3 signaling pathway, regulated the expression of related downstream proteins, and inhibited the proliferation and promoted the apoptosis of CD69+CD103+CD8+ TRM cells. For the first time, P53 was found to act as a downstream molecule of the JAK3/STAT3 pathway and was regulated by IRG1/itaconate to promote the apoptosis of CD8+ TRM cells. IRG1/itaconate can alleviate concanavalin A-induced autoimmune hepatitis in mice by inhibiting the proliferation and promoting the apoptosis of CD69+CD103+CD8+ TRM cells via the JAK3/STAT3/P53 pathway.

Investigating the role of itaconate in macrophage activation and oxidative stress injury in sepsis-associated acute kidney injury.

BACKGROUND: Sepsis may be linked to oxidative stress and can be controlled by itaconate, an activator of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Nevertheless, the itaconate impact on sepsis-associated acute kidney injury (SA-AKI) has yet to be definitively established. METHODS: We employed SA-AKI mouse model through a cecal ligation and puncture (CLP) procedure for the in vivo investigation of the potential nephroprotective effect of itaconate in this study. A plasmid was transfected into RAW264.7 cells to examine the Nrf2 pathway function after itaconate administration. Finally, the immune-responsive gene 1-knockout (IRG1-/-) mice were used to study the itaconate impacts on oxidative stress-induced SA-AKI. RESULTS: We have shown that 4-octyl itaconate (OI) significantly reduced CD11b-positive macrophage aggregation and activated the Nrf2 pathway in the bone marrow-derived macrophages (BMDM). The impacts of Nrf2 inhibitor ML385 on the anti-inflammatory and antioxidant properties of itaconate were found to be partial. OI inhibited lipopolysaccharide-induced oxidative stress injury in RAW264.7 macrophages and activated Nrf2 in the nucleus to hinder the expression of nuclear factor kappa B p65, thereby suppressing oxidative stress injury in the macrophages. Additionally, the introduction of the transfected plasmid resulted in a partial inhibition of the anti-inflammatory impact of itaconate. The kidney injury caused by sepsis exhibited greater severity in the IRG1-/- mice than in the wild type mice. Exogenous OI partially attenuated the kidney injury induced by sepsis in the IRG1-/- mice and suppressed the oxidative stress injury in macrophages. CONCLUSIONS: This investigation offers new proof to support the itaconate function in the development and progression of SA-AKI and shows a new possible therapeutic agent for the SA-AKI treatment.

Interleukin-6 on postoperative day three as an early predictor of infections following laparoscopic gastric cancer resection.

BACKGROUND: To investigate the role of C-reactive protein (CRP), procalcitonin (PCT), and interleukin-6 (IL-6) as early predictors of infectious complications after laparoscopic gastric cancer surgery. METHODS: Patients who underwent laparoscopic gastric cancer surgery between January 2020 and June 2022 were retrospectively enrolled. IL-6, PCT, and CRP levels were assessed before surgery and on postoperative days (PODs) 3 and 5. Differences in serum IL-6, PCT, and CRP levels between the infected and non-infected groups were compared. The diagnostic accuracy was determined using the area under the receiver operating characteristic curve (AUC). RESULTS: A total of 206 patients were enrolled, and 21 patients (10.19%) developed postoperative infections. Serum IL-6, PCT, and CRP levels in the infected group were significantly higher than those in the non-infected group on PODs 3 and 5. IL-6 with an optimal cutoff value of 84.00 pg/mL (AUC 0.84), PCT with an optimal cutoff value of 1.39 ng/mL (AUC 0.80), CRP with an optimal cutoff value of 150.00 mg/L (AUC 0.76) on POD 3 had superior diagnostic accuracy in predicting postoperative infections. Multivariate analysis identified PCT and IL-6 levels on POD 3 as independent risk factors, the AUC of the combination of IL-6 and PCT was 0.89. The Delong test showed no difference between the AUC of IL-6 alone and IL-6 combined with PCT prediction (P = 0.07, Z = 1.81). CONCLUSIONS: IL-6 level on POD 3 is an excellent predictor of infectious complications following laparoscopic gastric cancer surgery. Patients with IL-6 levels lower than 84.00 pg/mL on POD 3 can ensure safe early discharge with a low probability of infection.