The Mechanistic Target of Rapamycin Complex 1 Pathway Contributes to the Anti-Tumor Effect of Granulocyte-Macrophage-Colony-Stimulating Factor-Producing T Helper Cells in Mouse Colorectal Cancer.

INTRODUCTION: The role of granulocyte-macrophage-colony-stimulating factor-producing T helper (ThGM) cells in colorectal cancer (CRC) development remains unclear. This study characterizes the function of ThGM cells in mouse CRC. METHODS: Mouse CRC was induced by administrating azoxymethane and dextran sulfate sodium. The presence of ThGM cells in CRC tissues and the mechanistic target of rapamycin complex 1 (mTORC1) signaling in ThGM cells was detected by flow cytometry. The impact of mTORC1 signaling on ThGM cell function was determined by in vitro culture. The effect of ThGM cells on CRC development was evaluated by adoptive transfer assays. RESULTS: ThGM cells, which expressed granulocyte-macrophage-colony-stimulating factor (GM-CSF), accumulated in CRC tissues. mTORC1 signaling is activated in CRC ThGM cells. mTORC1 inhibition by rapamycin suppressed ThGM cell differentiation and proliferation and resulted in the death of differentiating ThGM cells. mTORC1 inhibition in already differentiated ThGM cells did not induce significant cell death but decreased the expression of GM-CSF, interleukin-2, and tumor necrosis factor-alpha while impeding cell proliferation. Furthermore, mTORC1 inhibition diminished the effect of ThGM cells on driving macrophage polarization toward the M1 type, as evidenced by lower expression of pro-inflammatory cytokines, major histocompatibility complex class II molecule, and CD80 in macrophages after co-culture with rapamycin-treated ThGM cells. Lentivirus-mediated knockdown/overexpression of regulatory-associated protein of mTOR (Raptor) confirmed the essential role of mTORC1 in ThGM cell differentiation and function. Adoptively transferred ThGM cells suppressed CRC growth whereas mTORC1 inhibition abolished this effect. CONCLUSION: mTORC1 is essential for the anti-CRC activity of ThGM cells.

Trends in the application of "omics" to Alzheimer's disease: a bibliometric and visualized study.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disease with an insidious onset. The widespread application of omics techniques in AD has attracted considerable attention. We aimed to make a comprehensive analysis of published omics articles on AD in order to determine the research profile and application trends of omics techniques in AD. METHODS: This study utilizes bibliometric and visual methods including a map collaboration map, co-citations, and keywords to identify knowledge structures, hot topics, and research trends based on 6,828 publications from the Web of Science Core Collection (WoSCC) database. RESULTS: The results of this study showed that 5654 institutions from 91 countries published articles in this field. The USA, China, and the UK played a leading role in publishing numerous articles in relevant journals as well as prolific institutions and authors, respectively. This paper collects a large number of literatures on the application of AD omics technology from the WoSCC database and found the omics technology applied to AD is mainly based on genomics technology. The application of transcriptomics technology has shown an increasing trend in recent years, and the application of multi-omics technology will be the general trend in the future. CONCLUSION: The development status, frontier hotspots, and general trends of omics application technologies are reviewed. This article will provide intelligence support to researchers and institutions in the field of Alzheimer's omics research and applications from a practical perspective.

Understanding the molecular pathogenesis of primary central nervous system lymphoma by experimental animal models.

Primary central nervous system lymphoma (PCNSL) is a rare and invasive diffuse large B cell lymphoma confined in central nervous system (CNS). The effort to press forward the translational progress has been frustrated by the insufficient understanding of immunophenotype of CNS and tumor genetic alterations of PCNSL, and the lack of validated diagnostic biomarkers. Researchers now have a variety of PCNSL animal models at their disposal that resemble the morphology and immunophenotype of PCNSL, however, a careful and detailed re-examination of these animal models is needed to clarify the differences in genetic alterations, migration capability, and immune status. In this review, we present the knowledge about the phenotypic and genotypic features of PCNSL tumor cells, and compile the preclinical animal models of PCNSL with regard to various injection sites, cell origins, recipient animals, and immune status, and elaborate on the tropism and migration of tumor cells and novel therapeutic strategies for PCNSL. We envisage that the selection of suitable animal models will serve as a well-defined preclinical system to understand the molecular pathogenesis of PCNSL, thereby galvanizing the development of novel and potent therapeutic approaches.

Sirtuin 2 up-regulation suppresses the anti-tumour activity of exhausted natural killer cells in mesenteric lymph nodes in murine colorectal carcinoma.

Natural killer (NK) cells inhibit colorectal carcinoma (CRC) initiation and progression through their tumoricidal activity. However, cumulative evidence suggests that NK cells become functionally exhausted in patients with CRC. To deepen the understanding of the mechanisms underlying CRC-associated NK cell exhaustion, we explored the expression and effect of Sirtuin 2 (Sirt2) in mesenteric lymph node (mLN) NK cells in a murine colitis-associated CRC model. Sirt2 was remarkably up-regulated in mLN NK cells after CRC induction. Particularly, Sirt2 was increased in mLN NK cells expressing high T cell immunoglobulin and mucin domain-3 (TIM3), high lymphocyte activation protein-3 (LAG3), high programmed death-1 (PD-1), high T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT), high NK group 2 member A (NKG2A), but low tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), low interferon-gamma and low granzyme B. In addition, Sirt2 was also increased in NK cells after induction of exhaustion in vitro. Lentivirus-mediated Sirt2 silencing did not affect the acute activation and cytotoxicity of non-exhausted NK cells. However, Sirt2 silencing partially restored the expression of interferon-gamma, granzyme B and CD107a in exhausted NK cells. Meanwhile, Sirt2 silencing down-regulated TIM3, LAG3, TIGIT and NKG2A while up-regulated TRAIL on exhausted NK cells. Consequently, Sirt2 silencing restored the cytotoxicity of exhausted NK cells. Moreover, Sirt2 silencing partially ameliorates the defects in glycolysis and mitochondrial respiration of exhausted NK cells, as evidenced by increases in glycolytic capacity, glycolytic reserve, basal respiration, maximal respiration and spare respiration capacity. Accordingly, Sirt2 negatively regulates the tumoricidal activity of exhausted NK cells in CRC.

Clinical significance of histopathological features of paired recurrent gliomas: a cohort study from a single cancer center.

OBJECTIVE: To explore the histopathological characteristics of paired recurrent gliomas and their clinical significance. METHODS: Glioma patients who received both primary surgery and reoperation when recurrence at Sun Yat-sen University Cancer Center from June 2001 to June 2019 were enrolled. Clinical and pathological characteristics were analyzed retrospectively, and histopathology of reoperation specimens was divided into three categories according to tumor cell activity and the degree of necrosis: active group, low-activity group, and necrosis group. RESULTS: A total of 89 patients were included in this study. The 2016 WHO grade of the first operation pathology and IDH1 status were related to survival time after the first operation, but there was no significant association with survival time after reoperation. The time interval between primary and reoperation was shorter for primary high-grade glioma and/or IDH1 wild-type tumor patients than for low-grade glioma and/or IDH1 mutant tumor patients (P < 0.001). Histopathological types of recurrent gliomas were analyzed, and 67 cases (75.3%) were classified into the active group, 14 (15.8%) into the low-activity group, and 8 (8.9%) into the necrosis group. The low-activity or necrosis group was associated with a higher radiotherapy dose and shorter operation interval. Further univariate and multivariate Cox survival analyses showed the histopathological patterns of recurrent gliomas to be related to survival time after reoperation. CONCLUSION: Primary WHO low grade or IDH1 mutant gliomas appeared survival benefit mainly on later recurrence, but was not a prognostic predictor following recurrence. Histopathological feature of recurrent glioma is related to previous treatment, including radiotherapy dosage and chemotherapy treatment, and is also an important independent prognostic factor for patients after reoperation.

Patched 1 and C-C Motif Chemokine Receptor 6 Distinguish Heterogeneous T Helper 17 Subsets in Colitic Lamina Propria.

T helper 17 (Th17) cells contribute to the pathogenesis of inflammatory bowel diseases (IBD). However, their heterogeneity and regulatory mechanisms in IBD are not completely disclosed. A mouse colitis model was established. Th17 cells were enriched from the mesenteric lymph nodes (mLN) and lamina propria (LP). The phenotypes and functions of Th17 subsets were analyzed by flow cytometry, Immunoblotting, and real-time RT-PCR. The contributions of the Th17 subsets to colitis pathogenesis were evaluated by histology, ELISA, and flow cytometry after adoptive transfer. Smoothened (SMO), GLI family zinc finger 1 (Gli1), and GLI family zinc finger 3 (Gli3) were markedly up-regulated while Patched 1 (PTCH1) was down-regulated in LP Th17 cells in colitic lamina propria. Based on the expression of PTCH1 and C-C motif chemokine receptor 6 (CCR6), LP Th17 cells were divided into a PTCH1lowCCR6low Th17 subset and a PTCH1highCCR6high Th17 subset. The former expressed higher T-bet, IFN-γ, TNF-α, IL-1ß, and GM-CSF but lower IL-17A, IL-22, IL-17F, and Gli3 than the latter. The PTCH1highCCR6high Th17 subset was more resistant to polarization towards T helper 1 (Th1) than the PTCH1lowCCR6low Th17 subset. Moreover, the PTCH1highCCR6high Th17 subset was more competent to maintain Th17 identity. The PTCH1highCCR6high Th17 subset induced less severe colitis than the PTCH1lowCCR6low Th17 subset. PTCH1highCCR6high Th17 cells are Th17 cells whereas PTCH1lowCCR6low Th17 cells are Th1-like Th17 cells. Our study deepens the understanding of Th17 heterogeneity and plasticity in colitis.

Bavachin protects against diet-induced hepatic steatosis and obesity in mice.

Non-alcoholic fatty liver disease (NAFLD) is a major health concern worldwide, and the incidence of metabolic disorders associated with NAFLD is rapidly increasing because of the obesity epidemic. There are currently no approved drugs that prevent or treat NAFLD. Recent evidence shows that bavachin, a flavonoid isolated from the seeds and fruits of Psoralea corylifolia L., increases the transcriptional activity of PPARγ and insulin sensitivity during preadipocyte differentiation, but the effect of bavachin on glucose and lipid metabolism remains unclear. In the current study we investigated the effects of bavachin on obesity-associated NAFLD in vivo and in vitro. In mouse primary hepatocytes and Huh7 cells, treatment with bavachin (20 µM) significantly suppressed PA/OA or high glucose/high insulin-induced increases in the expression of fatty acid synthesis-related genes and the number and size of lipid droplets. Furthermore, bavachin treatment markedly elevated the phosphorylation levels of AKT and GSK-3ß, improving the insulin signaling activity in the cells. In HFD-induced obese mice, administration of bavachin (30 mg/kg, i.p. every other day for 8 weeks) efficiently attenuated the increases in body weight, liver weight, blood glucose, and liver and serum triglyceride contents. Moreover, bavachin administration significantly alleviated hepatic inflammation and ameliorated HFD-induced glucose intolerance and insulin resistance. We demonstrated that bavachin protected against HFD-induced obesity by inducing fat thermogenesis and browning subcutaneous white adipose tissue (subWAT). We revealed that bavachin repressed the expression of lipid synthesis genes in the liver of obese mice, while promoting the expression of thermogenesis, browning, and mitochondrial respiration-related genes in subWAT and brown adipose tissue (BAT) in the mice. In conclusion, bavachin attenuates hepatic steatosis and obesity by repressing de novo lipogenesis, inducing fat thermogenesis and browning subWAT, suggesting that bavachin is a potential drug for NAFLD therapy.

Effect of O-arm on reduction quality and functional recovery of acetabular dome impaction fractures: a retrospective clinical study.

BACKGROUND: Acetabular dome impaction fractures (ADIF) are difficult to reduce and have a high failure rate. Consistency between the acetabulum and the femoral head is usually assessed using intraoperative X-ray fluoroscopy to evaluate the quality of fracture reduction. This study examines the effects of intraoperative mobile 2D/3DX imaging system (O-arm) on the reduction quality and functional recovery of ADIF. METHODS: We retrospectively analysed the data of 48 patients with ADIF treated at Honghui Hospital between October 2018 and October 2021.The patients were divided into the X-ray and O-arm groups. The residual step-off and gap displacements in the acetabular dome region were measured, and fracture reduction quality was evaluated. Hip function was evaluated using the modified Merle d'Aubigné and Postel scoring systems. RESULTS: There were no significant intergroup differences in the preoperative general data (p > 0.05). The mean residual average step displacement in the acetabular dome region was 3.48 ± 2.43 mm and 1.61 ± 1.16 mm (p < 0.05), while the mean gap displacement was 6.72 ± 3.69 mm and 3.83 ± 1.67 mm (p < 0.05) in the X-ray and the O-arm groups, respectively. In the X-ray group, according to the fracture reduction criteria described by Verbeek and Moed et al., one case was excellent, 13 cases were good, 11 cases were poor; 56% were excellent or good. In the O-arm group, seven cases were excellent, 12 cases were good, and four cases were poor; overall in this group, 82.6% were excellent or good (p < 0.05). A total of 46 patients achieved fracture healing at the last follow-up. In the X-ray group, according to the modified Merle d'Aubigné and Postel function score, three cases were excellent,12 cases were good, six cases were middle, three cases were poor; 62.5% were excellent or good, In the O-arm group, 15 cases were excellent, four cases were good, two cases were middle, one case was poor; 86.4% were excellent or good (p < 0.05). CONCLUSIONS: The application of O-arm in ADIF can improve fracture reduction quality and functional recovery.

Driver mutations in ADGRL3 are involved in the evolution of ependymoma.

Although there have been recent advances in the molecular pathology of ependymomas, little is known about the underlying molecular evolution during its development. Here, we assessed the clinical, pathological and molecular evolutionary process of ependymoma recurrence in a 9-year-old patient who had seven recurrences of supratentorial ependymoma and died from intracranial multiregional recurrences at the age of 19 years old. Whole-genome sequencing (WGS) of 7 tumor samples (1 primary and 6 subsequent recurrent tumors) was performed to elucidate the mutation landscape and identify potential driver mutations for tumor evolution. The genetic profiles of the seven tumor specimens showed significant heterogeneity and suggested a highly branched evolutionary pattern. The mutational signatures and chromothripsis changed with treatments. Strikingly, adhesion G protein-coupled receptor L3 (ADGRL3, also known as Latrophilins 3, LPNH3) was found to be consistently mutated during the entire disease process. However, Sanger sequencing of other 78 ependymoma patients who underwent surgery at our institution showed no genetic alteration of ADGRL3, as found in the present case. The mRNA levels of ADGRL3 were significantly lower in ependymomas (n = 36), as compared with normal brain tissue (n = 3). Grade III ependymomas had the lowest ADGRL3 expression. Moreover, ependymomas with lower mRNA level of ADGRL3 had shorter overall survival. Our findings, therefore, demonstrate a rare evolutionary process of ependymoma involving ADGRL3.

Deep learning-based automatic segmentation of meningioma from multiparametric MRI for preoperative meningioma differentiation using radiomic features: a multicentre study.

OBJECTIVES: Develop and evaluate a deep learning-based automatic meningioma segmentation method for preoperative meningioma differentiation using radiomic features. METHODS: A retrospective multicentre inclusion of MR examinations (T1/T2-weighted and contrast-enhanced T1-weighted imaging) was conducted. Data from centre 1 were allocated to training (n = 307, age = 50.94 ± 11.51) and internal testing (n = 238, age = 50.70 ± 12.72) cohorts, and data from centre 2 external testing cohort (n = 64, age = 48.45 ± 13.59). A modified attention U-Net was trained for meningioma segmentation. Segmentation accuracy was evaluated by five quantitative metrics. The agreement between radiomic features from manual and automatic segmentations was assessed using intra class correlation coefficient (ICC). After univariate and minimum-redundancy-maximum-relevance feature selection, L1-regularized logistic regression models for differentiating between low-grade (I) and high-grade (II and III) meningiomas were separately constructed using manual and automatic segmentations; their performances were evaluated using ROC analysis. RESULTS: Dice of meningioma segmentation for the internal testing cohort were 0.94 ± 0.04 and 0.91 ± 0.05 for tumour volumes in contrast-enhanced T1-weighted and T2-weighted images, respectively; those for the external testing cohort were 0.90 ± 0.07 and 0.88 ± 0.07. Features extracted using manual and automatic segmentations agreed well, for both the internal (ICC = 0.94, interquartile range: 0.88-0.97) and external (ICC = 0.90, interquartile range: 0.78-70.96) testing cohorts. AUC of radiomic model with automatic segmentation was comparable with that of the model with manual segmentation for both the internal (0.95 vs. 0.93, p = 0.176) and external (0.88 vs. 0.91, p = 0.419) testing cohorts. CONCLUSIONS: The developed deep learning-based segmentation method enables automatic and accurate extraction of meningioma from multiparametric MR images and can help deploy radiomics for preoperative meningioma differentiation in clinical practice. KEY POINTS: • A deep learning-based method was developed for automatic segmentation of meningioma from multiparametric MR images. • The automatic segmentation method enabled accurate extraction of meningiomas and yielded radiomic features that were highly consistent with those that were obtained using manual segmentation. • High-grade meningiomas were preoperatively differentiated from low-grade meningiomas using a radiomic model constructed on features from automatic segmentation.