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More and more studies had pointed out that the tumor microenvironment characteristics based on colorectal cancer (CRC) pretreatment biopsy specimens could effectively predict the efficacy of neoadjuvant therapy, but under hematoxylin and eosin (HE) staining, whether the tumor microenvironment characteristics observed by pathologists could predict the efficacy of neoadjuvant therapy remains to be discussed. We collected 106 CRC patients who received neoadjuvant treatment and surgical resection from 3 hospitals. The number of mitosis, inflammation degree, desmoplastic reaction (DR), necrosis, tumor-stroma ratio (TSR) and tumor budding (TB) of CRC pretreatment biopsy specimens were observed under HE staining, and the degree of tumor pathological remission of CRC surgical specimens after neoadjuvant treatment was evaluated. According to the tumor regression grade (TRG), patients were divided into good-responders (TRG 0-1) and non-responders (TRG 2-3). All data were analyzed with SPSS software (version 23.0) to evaluate the correlation between the number of mitosis, inflammation degree, DR, necrosis, TSR and TB in pretreatment biopsy samples and the treatment effect. In univariate analysis, mitosis (P = .442), inflammation degree (P = .951), DR (P = .186), necrosis (P = .306), TSR (P = .672), and TB (P = .327) were not associated with the response to neoadjuvant therapy. However, we found that for colon cancer, rectal cancer was more likely to benefit from neoadjuvant therapy (P = .024). In addition, we further analyzed the impact of mitosis, inflammation degree, DR, necrosis, TSR and TB on neoadjuvant therapy in rectal cancer, and found that there was no predictive effect. By analyzing the characteristics of tumor microenvironment of CRC pretreatment biopsy specimens under HE staining, such as mitosis, inflammation degree, DR, necrosis, TSR and TB, it was impossible to effectively predict the efficacy of neoadjuvant therapy for CRC., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Intestinal immune dysregulation is strongly linked to the occurrence and formation of tumors. RING finger protein 128 (RNF128) has been identified to play distinct immunoregulatory functions in innate and adaptive systems. However, the physiological roles of RNF128 in intestinal inflammatory conditions such as colitis and colorectal cancer (CRC) remain controversial., Objectives: To elucidate the function and mechanism of RNF128 in colitis and CRC., Methods: Animal models of dextran sodium sulfate (DSS)-induced colitis and azoxymethane (AOM)/DSS-induced CRC were established in WT and Rnf128-deficient mice and evaluated by histopathology. Co-immunoprecipitation and ubiquitination analyses were employed to investigate the role of RNF128 in IL-6-STAT3 signaling., Results: RNF128 was significantly downregulated in clinical CRC tissues compared with paired peritumoral tissues. Rnf128-deficient mice were hypersusceptible to both colitis induced by DSS and CRC induced by AOM/DSS or APC mutation. Loss of RNF128 promoted the proliferation of CRC cells and STAT3 activation during the early transformative stage of carcinogenesis in vivo and in vitro when stimulated by IL-6. Mechanistically, RNF128 interacted with the IL-6 receptor α subunit (IL-6Rα) and membrane glycoprotein gp130 and mediated their lysosomal degradation in ligase activity-dependent manner. Through a series of point mutations in the IL-6 receptor, we identified that RNF128 promoted K48-linked polyubiquitination of IL-6Rα at K398/K401 and gp130 at K718/K816/K866. Additionally, blocking STAT3 activation effectively eradicated the inflammatory damage of Rnf128-deficient mice during the transformative stage of carcinogenesis., Conclusion: RNF128 attenuates colitis and colorectal tumorigenesis by inhibiting IL-6-STAT3 signaling, which sheds novel insights into the modulation of IL-6 receptors and the inflammation-to-cancer transition., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Production and hosting by Elsevier B.V.)

Candida albicans is among the most prevalent invasive fungal pathogens for immunocompromised individuals and novel therapeutic approaches that involve immune response modulation are imperative. Absent in melanoma 2 (AIM2), a pattern recognition receptor for DNA sensing, is well recognized for its involvement in inflammasome formation and its crucial role in safeguarding the host against various pathogenic infections. However, the role of AIM2 in host defense against C. albicans infection remains uncertain. This study reveals that the gene expression of AIM2 is induced in human and mouse innate immune cells or tissues after C. albicans infection. Furthermore, compared to their wild-type (WT) counterparts, Aim2 -/- mice surprisingly exhibit resistance to C. albicans infection, along with reduced inflammation in the kidneys post-infection. The resistance of Aim2 -/- mice to C. albicans infection is not reliant on inflammasome or type I interferon production. Instead, Aim2 -/- mice display lower levels of apoptosis in kidney tissues following infection than WT mice. The deficiency of AIM2 in macrophages, but not in dendritic cells, results in a phenocopy of the resistance observed in Aim2 -/- mice against C. albican infection. The treatment of Clodronate Liposome, a reagent that depletes macrophages, also shows the critical role of macrophages in host defense against C. albican infection in Aim2 -/- mice. Furthermore, the reduction in apoptosis is observed in Aim2 -/- mouse macrophages following infection or treatment of DNA from C. albicans in comparison with controls. Additionally, higher levels of AKT activation are observed in Aim2 -/- mice, and treatment with an AKT inhibitor reverses the host resistance to C. albicans infection. The findings collectively demonstrate that AIM2 exerts a negative regulatory effect on AKT activation and enhances macrophage apoptosis, ultimately compromising host defense against C. albicans infection. This suggests that AIM2 and AKT may represent promising therapeutic targets for the management of fungal infections., (© 2024. The Author(s).)

IFN regulatory factor 7 (IRF7) exerts anti-infective effects by promoting the production of IFNs in various bacterial and viral infections, but its role in highly morbid and fatal Candida albicans infections is unknown. We unexpectedly found that Irf7 gene expression levels were significantly upregulated in tissues or cells after C. albicans infection in humans and mice and that IRF7 actually exacerbates C. albicans infection in mice independent of its classical function in inducing IFNs production. Compared to controls, Irf7-/- mice showed stronger phagocytosis of fungus, upregulation of C-type lectin receptor CD209 expression, and enhanced P53-AMPK-mTOR-mediated autophagic signaling in macrophages after C. albicans infection. The administration of the CD209-neutralizing Ab significantly hindered the phagocytosis of Irf7-/- mouse macrophages, whereas the inhibition of p53 or autophagy impaired the killing function of these macrophages. Thus, IRF7 exacerbates C. albicans infection by compromising the phagocytosis and killing capacity of macrophages via regulating CD209 expression and p53-AMPK-mTOR-mediated autophagy, respectively. This finding reveals a novel function of IRF7 independent of its canonical IFNs production and its unexpected role in enhancing fungal infections, thus providing more specific and effective targets for antifungal therapy., (Copyright © 2024 by The American Association of Immunologists, Inc.)

Candida albicans is a common opportunistic pathogenic fungus. The innate immune system provides the first-line host defense against fungal infection. Innate immune receptors and downstream molecules have been shown to play various roles during fungal infection. The innate immune receptor MDA5, encoded by the gene Ifih1, enhances host resistance against viral and Aspergillus fumigatus infection by inducing the production of interferons (IFNs). However, the role of MDA5 in C. albicans infection is still unclear. Here, we found that the gene expression levels of IFIH1 were significantly increased in innate immune cells after C. albicans stimulation through human bioinformatics analysis or mouse experiments. Through in vivo study, MDA5 was shown to enhance host susceptibility to C. albicans infection independent of IFN production. Instead, MDA5 exerted its influence on macrophages and kidneys by modulating the expression of Noxa, Bcl2, and Bax, thereby promoting apoptosis. Additionally, MDA5 compromised killing capabilities of macrophage by inhibition iNOS expression. The introduction of the apoptosis inducer PAC1 further impaired macrophage functions, mimicking the enhancing effect of MDA5 on C. albicans infection. Furthermore, the administration of macrophage scavengers increased the susceptibility of Ifih1 -/- mice to C. albicans. The founding suggests that MDA5 promote host susceptibility to invasive C. albicans by enhancing cell apoptosis and compromising macrophage functions, making MDA5 a target to treat candidiasis., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: The aims of this study are to screen novel differentially expressed genes (DEGs) for intracerebral hemorrhage (ICH) and reveal the role of Lipocalin-2 (LCN2) in ICH., Methods: We constructed the ICH model by injection of autologous whole blood into the right basal ganglia in rats. RNA-sequencing and bioinformatics analyses were performed to identify the DEGs between ICH and sham rats, and some important ones were confirmed using quantitative real-time PCR (qRT-PCR). LCN shRNA was used to knockdown of LCN2 in ICH rats. Pathological examination was carried out using 2,3,5-triphenyltetrazolium chloride (TTC) staining and Hematoxylin-eosin (HE) staining. Immunohistochemistry detected Caspase-3, and co-staining of Terminal dUTP nick end labeling (TUNEL) and NEUN staining were performed for neuron apoptosis assessment. Western blot analysis was performed to quantify pyroptosis-related proteins. Enzyme-linked immunosorbent assay (ELISA) was used to measure inflammatory cytokine levels., Results: ICH rats exhibited significant hematomas, higher brain water content, obvious interstitial edema, and inflammatory infiltration, as well as more apoptotic cells in brain tissues. RNA-seq analysis identified 103 upregulated and 81 downregulated DEGs. The expression of LCN2, HSPB1, CXCL10, and MEF2B were upregulated in ICH rats. ICH triggered the release of interleukin (IL)-1β, tumor necrosis factor-α (TNF-α), and IL-18, and promoted the expression of pyroptosis-related proteins Caspase-1, GSDMD, NLRP3, and ASC. LCN2 knockdown attenuated the pathological characteristics of ICH, and also reduced pyroptosis in brain tissues., Conclusion: Inhibition of LCN2 attenuates brain injury after ICH via suppressing pyroptosis, which provide guidance for ICH management., Competing Interests: The authors declare that they have no conflicts of interest to disclose., (© 2024 Zhao et al.)

Colorectal cancer (CRC) is a prevalent cause of cancer and mortality on a global scale. SNAI1, a member of the zinc finger transcription superfamily, is a significant contributor to embryonic development and carcinogenesis through the process of epithelial-mesenchymal transition (EMT). While prior research utilizing CRC cells and clinical data has demonstrated that SNAI1 facilitates CRC progression through diverse mechanisms, the precise manner in which epithelial SNAI1 regulates CRC development in vivo remains unclear. In this study, colitis and colitis-associated CRC were induced through the use of intestinal epithelium-specific Snai1 knockout (Snai1 cKO) mice. Our findings indicate that Snai1 cKO mice exhibit a reduced susceptibility to acute colitis and colitis-associated CRC compared to control mice. Western-blot analysis of colon tissues revealed that Snai1 cKO mice exhibited a higher overall apoptosis level during tumor formation than control mice. No significant differences were observed in the activation of the classical p53 signaling pathway. However, Snai1 cKO mice exhibited weakened EMT and Wnt/β-catenin pathway activation. In summary, our study has provided evidence in vivo that the intestinal epithelial SNAI1 protein suppresses apoptosis, amplifies the EMT, and activates the Wnt/β-catenin signaling pathways in both early and late phases of CRC formation, thus promoting the development and progression of colitis-associated CRC., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Gastric cancer (GC) is a prevalent digestive tract malignant tumor characterized by an insidious onset, ease of metastasis, rapid growth, and poor prognosis. Here, we report that fibronectin type III domain containing 1 (FNDC1) has high expression in GC and indicates poor outcomes in patients with GC. FNDC1 over-expression or knockdown promotes or inhibits tumorigenesis and metastasis, respectively. The expression of FNDC1 is upregulated by TWIST1, strengthening its interaction with Gβγ and VEGFR2. The formation of the trimers, TWIST1 plus Gβγ and VEGFR2, increases VEGFR2 phosphorylation and Gβγ trafficking, which activates RAS-MAPK and PI3K-AKT signaling, benefiting GC progression. In this study, we demonstrated that arsenite can efficiently suppress FNDC1 expression, attenuating the formation of the trimers and downstream pathways. Altogether, our results indicate that FNDC1 might be a promising target for clinical treatment and prognostic judgment, while FNDC1 inhibition by arsenite provides a new opportunity for overcoming this fatal disease., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors.)

Background: Chronic subdural hematoma (CSDH) is a common neurosurgical disease with a high recurrence rate, especially among the elderly. Glucocorticoids have been tested for the treatment of CSDH in observational studies and randomized clinical trials., Methods: We systematically searched the PubMed, Embase, and Cochrane Central Register of Controlled Trials database for randomized trials from the earliest date available to May 23, 2021 that had compared glucocorticoids and placebo as a postoperative treatment of CSDH. Trials were included if the study participants were aged ≥18 years and had had CSDH after surgery. The relative risk (RR) was used to evaluate the clinical outcomes., Results: We included 5 eligible randomized controlled trials with a total of 1251 patients. The findings showed that the use of adjuvant glucocorticoid therapy can effectively reduce the recurrence risk of CSDH compared with placebo (RR, 0.40; 95% confidence interval [CI], 0.28-0.58; P < 0.001). No significant differences were found between the glucocorticoid and placebo groups regarding favorable neurological outcomes (RR, 1; 95% CI, 0.93-1.08; P = 0.92). We found that the use of adjuvant glucocorticoids resulted in a significant increase in psychiatric symptoms (RR, 3.22; 95% CI, 1.83-5.64; P < 0.001). No significant differences were found for infection between the 2 groups (RR, 1.86; 95% CI, 0.56-6.14; P = 0.31)., Conclusions: Glucocorticoid therapy can effectively reduce the recurrence risk of CSDH after surgery without an increase in the postoperative infection rate. However, significantly increased psychiatric symptoms were reported in the glucocorticoid group., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Colorectal cancer (CRC) is one of the most common digestive tract malignancies and inflammation and gut microbiota are well-known key factors to influence CRC development. Akkermansia mucinipila is an important gram-negative anaerobic bacterium that can degrade mucin in gut. Previous studies suggested that A. muciniphila may affect inflammation and cell proliferation, but the relationship between A. muciniphila and CRC is not clarified. Here C57BL/6 mice were administrated with A. muciniphila or PBS and then treated with azoxymethane (AOM)/dextran sodium sulphate (DSS) to induce CRC. The mice receiving A. muciniphila administration had more serious weight loss, shorter colon length and more intestinal tumors than those receiving PBS administration after AOM/DSS treatment. More colon damage and less goblet cells were also observed in A. muciniphila treated mice. Furthermore, A. muciniphila administration induced more Ki67 + proliferating cells, higher PCNA expression and elevated gene expression of proliferation-associated molecules including Snrpd1 , Dbf4 or S100A9 . At early stage of CRC development, in comparison with controls, the mice receiving A. muciniphila administration also had more body weight loss and shorter colon length, as well as higher gene expression of inflammatory cytokines. Furthermore, the in vitro experimental results showed that the co-culture of colon epithelial cells with A. muciniphila enhanced the cell proliferation and gene expression of proliferation-associated molecules. Therefore, A. mucinipila may promote the formation of CRC in mice through increasing the early level of inflammation and the proliferation of intestinal epithelial cells., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Aneurysmal subarachnoid hemorrhage is a relatively rare cause of stroke, carrying a bad prognosis of mortality and disability. The current standard procedure, neurosurgical clipping, has failed to achieve satisfactory outcomes. Therefore, endovascular detachable coils have been tested as an alternative. This meta-analysis was aimed to compare the outcomes of surgical clipping and endovascular coiling in aneurysmal subarachnoid hemorrhage., Materials and Methods: Relevant randomized trials up to June 2018 were identified from Medline, Central, and Web of Science. Data for poor outcomes (Modified Rankin Scale [mRS] scores 3 to 6) at 2-3 months, 1 year, and 3-5 years were extracted and analyzed as odds ratios (ORs) with 95% confidence intervals (CIs), using RevMan software., Results: Five studies (2780: 1393 and 1387 patients in the coiling and clipping arms, respectively) were included in the current analysis. The overall effect estimate favored endovascular coiling over surgical clipping in terms of reducing poor outcomes (death or dependency, mRS > 2) at 1 year (OR = 0.67, 95% CI: 0.57-0.79) and 3-5 years (OR = 0.8, 95% CI: 0.67-0.96). Moreover, coiling was associated with a significantly lower rate of cerebral ischemia (OR = 0.37, 95% CI: 0.16-0.86). Postprocedural mortality (OR = 0.79, 95% CI: 0.6-1.05) and rebleeding (OR = 1.15, 95% CI: 0.75-1.78) rates were comparable between the two groups. However, technical failure was significantly more common with coiling interventions than with clipping surgeries (OR = 2.84, 95% CI: 1.86-4.34)., Conclusion: Our analysis suggests that coiling can be a better alternative to clipping in terms of surgical outcomes. Further improvements in the coiling technique and training may improve the outcomes of this procedure., Competing Interests: There are no conflicts for interest., (Copyright: © 2019 Journal of Research in Medical Sciences.)

Glioblastoma is one of the most common primary brain tumors in adults. The current treatment strategies failed to achieve satisfactory outcomes. Anti-vascular endothelial growth factor (anti-VEGF) agents have been proposed to enhance the survival and quality of life in these patients. To investigate this, different databases were searched in addition to hand searching. Relevant studies were screened and only ten randomized controlled trials (RCTs) met the eligibility criteria; six of them were considered for meta-analysis. Eligible RCTs were assessed regarding risk of bias using the Cochrane tool. Relevant data were extracted and meta-analysis was conducted using the random effects model analysis on RevMan software. One thousand seventy-eight patients in the anti-VEGF group and 946 patients in the control group were available for analysis. No statistically significant improvement in the overall survival (OS) was detected for anti-VEGF (OR 0.87, 95% CI 0.7-1.09, p = 0.23) or bevacizumab subgroup (OR 0.84, 95% CI 0.65-1.08, p = 0.17) compared to standard therapy alone. However, the progression-free survival (PFS) showed a significant improvement with both anti-VEGF (OR 0.76, 95% CI 0.65-0.89, p = 0.0007) and bevacizumab subgroup (OR 0.75, 95% CI 0.65-0.87, p = 0.0001). In conclusion, anti-VEGF agents can improve the PFS but not OS in glioblastoma patients. The current evidence is not satisfactory to declare a new therapeutic line. Further RCTs with sharply determined outcomes and assessment methods are required.