AURKB promotes colorectal cancer progression by triggering the phosphorylation of histone H3 at serine 10 to activate CCNE1 expression.

Aurora kinase B (AURKB) initiates the phosphorylation of serine 10 on histone H3 (pH3S10), a crucial process for chromosome condensation and cytokinesis in mammalian mitosis. Nonetheless, the precise mechanisms through which AURKB regulates the cell cycle and contributes to tumorigenesis as an oncogenic factor in colorectal cancer (CRC) remain unclear. Here, we report that AURKB was highly expressed and positively correlated with Ki-67 expression in CRC. The abundant expression of AURKB promotes the growth of CRC cells and xenograft tumors in animal model. AURKB knockdown substantially suppressed CRC proliferation and triggered cell cycle arrest in G2/M phase. Interestingly, cyclin E1 (CCNE1) was discovered as a direct downstream target of AURKB and functioned synergistically with AURKB to promote CRC cell proliferation. Mechanically, AURKB activated CCNE1 expression by triggering pH3S10 in the promoter region of CCNE1. Furthermore, it was showed that the inhibitor specific for AURKB (AZD1152) can suppress CCNE1 expression in CRC cells and inhibit tumor cell growth. To conclude, this research demonstrates that AURKB accelerated the tumorigenesis of CRC through its potential to epigenetically activate CCNE1 expression, suggesting AURKB as a promising therapeutic target in CRC.

Effect of the supplementation of exogenous complex non-starch polysaccharidases on the growth performance, rumen fermentation and microflora of fattening sheep.

The objective of this study was to evaluate the effects of exogenous non-starch polysaccharidases (a mixture of cellulase, xylanase, ß-glucanase and mannanase) on the growth performance and nutrient digestibility, rumen fermentation, and rumen microflora of sheep. The animal trial was conducted using 36 5-month-old female fattening hybrid sheep (Duolang♂ × Hu♀) who were randomly assigned into four groups comprising nine sheep per treatment: CON, T1, T2, and T3, with 0, 0.1, 0.3, and 0.5% NSPases/kg DM of TMR, respectively. This complex enzyme product was screened for optimal ratios based on previous in vitro tests and responded positively to the in vitro fermentation of the TMR. When treated with NSPases, there was a non-linear effect of average daily gain and feed conversion rate, with the greatest improvement observed in the T2 group. There were no significant differences (p > 0.05) in nutrient intake or apparent digestibility among the NSPase-supplemented groups. In addition, T2 group had a significantly higher acetate to propionate ratio and pH (p < 0.05) than the other groups, and NH3-N and microbial protein concentrations showed a quadratic curve. The results revealed that both immunoglobulins and serum hormones increased linearly with addition (p < 0.05). As the T2 group showed the best growth performance, the CON and T2 groups were subjected to rumen metagenomic analysis. The results showed higher abundance of bacteria and lower abundance of Viruses in the rumen microbiota of the T2 group compared to the CON group. In addition, Uroviricota and Proteobacteria abundance was significantly lower in the T2 group than in the CON group at the phylum level (p < 0.05). These results suggest that the supplementation of high-concentrate rations with NSPases enhance immunity, reduces virus abundance in the rumen, improves rumen health, and promotes rumen fermentation. Our findings provide novel insights for improving growth performance and alleviating inflammatory responses arising from high concentrate feeding patterns in ruminants. However, the biological mechanisms cannot be elucidated by exploring the composition of rumen microbe alone, and further studies are required.

Tumor neoantigens derived from RNA editing events show significant clinical relevance in melanoma patients treated with immunotherapy.

This study aimed to investigate the clinical significance of RNA editing (RE) and RNA editing derived (RED-) neoantigens in melanoma patients treated with immunotherapy. Vardict and VEP were used to identify the somatic mutations. RE events were identified by Reditools2 and filtered by the custom pipeline. miRTar2GO was implemented to predict the RE whether located in miRNA targets within the 3' UTR region. NetMHCpan and NetCTLpan were used to identify and characterize RED-neoantigens. In total, 7116 RE events were identified, most of which were A-to-I events. Using our custom pipeline, 631 RED-neoantigens were identified that show a significantly greater peptide-MHC affinity, and facilitate epitope processing and presentation than wild-type peptides. The OS of the patients with high RED-neoantigens burden was significantly longer ( P  = 0.035), and a significantly higher RED-neoantigens burden was observed in responders ( P  = 0.048). The area under the curve of the RED-neoantigen was 0.831 of OS. Then, we validated the reliability of RED-neoantigens in predicting the prognosis in an independent cohort and found that patients with high RED-neoantigens exhibited a longer OS ( P  = 0.008). To our knowledge, this is the first study to systematically assess the clinical relevance of RED-neoantigens in melanoma patients treated with immunotherapy.

Syntaphilin Inactivation Can Enhance Axonal Mitochondrial Transport to Improve Spinal Cord Injury.

Mitochondria are important organelle of eukaryotic cells. They consists of a large number of different proteins that provide most of the ATP and supply power for the growth, function, and regeneration of neurons. Therefore, smitochondrial transport ensures that adequate ATP is supplied for metabolic activities. Spinal cord injury (SCI), a detrimental condition, has high morbidity and mortality rates. Currently, the available treatments only provide symptomatic relief for long-term disabilities. Studies have implicated mitochondrial transport as a critical factor in axonal regeneration. Hence, enhancing mitochondrial transports could be beneficial for ameliorating SCI. Syntaphilin (Snph) is a mitochondrial docking protein that acts as a "static anchor," and its inhibition enhances mitochondrial transports. Therefore, Snph as a key mediator of mitochondrial transports, may contribute to improving axonal regeneration following SCI. Herein, we examine Snph's biological effects and its relation to mitochondrial pathway. Then, we elaborate on mitochondrial transports after SCI, the possible role of Snph in SCI, and some possible therapeutic approaches by Snph.

Quercetin activates the Sestrin2/AMPK/SIRT1 axis to improve amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disease with poor prognosis. The intricacies surrounding its pathophysiology could partly account for the lack of effective treatment for ALS. Sestrin2 has been reported to improve metabolic, cardiovascular and neurodegenerative diseases, and is involved in the direct and indirect activation of the adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/silent information regulator 1 (SIRT1) axis. Quercetin, as a phytochemical, has considerable biological activities, such as anti-oxidation, anti-inflammation, anti-tumorigenicity, and neuroprotection. Interestingly, quercetin can activate the AMPK/SIRT1 signaling pathway to reduce endoplasmic reticulum stress, and alleviate apoptosis and inflammation. This report examines the molecular relationship between Sestrin2 and AMPK/SIRT1 axis, as well as the main biological functions and research progress of quercetin, together with the correlation between quercetin and Sestrin2/AMPK/SIRT1 axis in neurodegenerative diseases.

Comprehensive Multiomics Analysis Identified IQGAP3 as a Potential Prognostic Marker in Pan-Cancer.

Background: IQGAP3 has important function in cancer progression and has become a potential therapeutic target as a transmembrane protein. But its role in tumor immunity and pan-cancer was not systematically investigated. This study evaluated the potential role of IQGAP3 and clinical significance in pan-cancer through combined multiomics analysis. Methods: From Genotype Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) databases, transcriptomic datasets were first obtained, and from Gene Expression Omnibus (GEO), expression profiling microarray data were acquired and integrated to systematically assess the expression differences and prognostic relevance of IQGAP3 in pancreatic cancer. Immunohistochemical data were obtained from Human Protein Atlas (HPA) to assess IQGAP3 protein expression differences, and exome data from TCGA were used to analyze IQGAP3 expression in relation to tumor mutational burden (TMB), microsatellite instability (MSI), and mutation. Additionally, we also analyzed the relationship between IQGAP3 expression and immune checkpoints, mismatch repair (MMR), and IQGAP3 relationship with methylation and copy number variation based on expression profiles. Results: Microsatellite instability (MSI), immune checkpoints, mismatch repair (MMR), and tumor mutational burden (TMB) all closely interacted with IQGAP3 mRNA. In addition, detailed relationships between the immune microenvironment and IQGAP3 mRNA as well as immune cell CD4+ Th2 and myeloid-derived suppressor cells (MDSCs) were determined. Mechanistically, IQGAP3 was involved in cytoskeleton formation, T cell receptor signaling pathways, DNA damage, cell cycle, P53 pathway, Fc gamma R-mediated phagocytosis, and apoptosis. Conclusion: IQGAP3 could serve as an effective prognostic biomarker for pan-cancer immune-related therapy.

SARM1 can be a potential therapeutic target for spinal cord injury.

Injury to the spinal cord is devastating. Studies have implicated Wallerian degeneration as the main cause of axonal destruction in the wake of spinal cord injury. Therefore, the suppression of Wallerian degeneration could be beneficial for spinal cord injury treatment. Sterile alpha and armadillo motif-containing protein 1 (SARM1) is a key modulator of Wallerian degeneration, and its impediment can improve spinal cord injury to a significant degree. In this report, we analyze the various signaling domains of SARM1, the recent findings on Wallerian degeneration and its relation to axonal insults, as well as its connection to SARM1, the mitogen-activated protein kinase (MAPK) signaling, and the survival factor, nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2). We then elaborate on the possible role of SARM1 in spinal cord injury and explicate how its obstruction could potentially alleviate the injury.

Silencing of UBE2D1 inhibited cell migration in gastric cancer, decreasing ubiquitination of SMAD4.

BACKGROUND: Gastric cancer (GC) is the second leading cause of cancer-related deaths. Because it is hard to diagnose at early stage, the overall 5 years survival rate is lower than 25%. High migration is the main hallmark of malignant cells at advanced stage of GC. Thus, it is urgent to find biomarkers for early diagnosis and more effective therapy of GC. METHODS: In this study, lentivirus-mediated silencing and overexpression lentiviruses targeting the ubiquitin-conjugating enzyme E2 D1 (UBE2D1), transwell, wound healing, and pulmonary metastasis mouse model were applied to analyze the function of UBE2D1 in vitro and in vivo. Real-time PCR and immunohistochemistry were used to elucidate the level of UBE2D1 in GC samples. RESULTS: Silencing of UBE2D1 inhibited cell migration and the levels of epithelial-mesenchymal transition makers (MMP2 and MMP9) in AGS and MKN45 cells. Silencing of UBE2D1 inhibited cell metastasis in mouse model. On the contrary, UBE2D1 overexpression increased cell migration and the levels of MMP2 and MMP9 in MGC-803 cells. Further, silencing of UBE2D1 decreased the ubiquitination level of mothers against decapentaplegic homolog 4 (SMAD4), and the increase of cell migration induced by UBE2D1 overexpression could be reversed by SMAD4. CONCLUSION: Silencing of UBE2D1 inhibited cell migration through transforming growth factor ß (TGF-ß)/SMAD4 signaling pathway in GC.

Prognostic value of lymphovascular invasion in stage II colorectal cancer patients with an inadequate examination of lymph nodes.

BACKGROUND: Lymphovascular invasion (LVI) is defined as the presence of cancer cells in lymphatics or blood vessels. This study aimed to evaluate the prognostic value of LVI in stage II colorectal cancer (CRC) patients with inadequate examination of lymph nodes (ELNs) and further combined LVI with the TNM staging system to determine the predictive efficacy for CRC prognosis. Adjuvant chemotherapy (ACT) was then evaluated for stage II CRC patients with LVI positivity (LVI+). METHODS: In order to avoid the effects of different ACT regimens, among 409 stage II patients, we chose 121 patients who received FOLFOX regimen and the 144 patients who did not receive ACT as the object of study. LVI was examined by hematoxylin-eosin (HE) staining. Kaplan-Meier analysis followed by a log-rank test was used to analyze survival rates. Univariate and multivariate analyses were performed using a Cox proportional hazards model. Harrell's concordance index (C-index) was used to evaluate the accuracy of different systems in predicting prognosis. RESULTS: The LVI+ status was significantly associated with pT stage, degree of differentiation, tumor stage, serum CEA and CA19-9 levels, perineural invasion (PNI), tumor budding (TB), and KRAS status. The 5-year overall survival (OS) rate of stage II patients with < 12 ELNs and LVI+ was less than stage IIIA. Multivariate analyses showed that LVI, pT-stage, serum CEA and CA19-9 levels, PNI, TB, and KRAS status were significant prognostic factors for stage II patients with < 12 ELNs. The 8th TNM staging system combined with LVI showed a higher C-index than the 8th TNM staging system alone (C-index, 0.895 vs. 0.833). Among patients with LVI+, the ACT group had a significantly higher 5-year OS and 5-year disease-free survival (DFS) than the surgery alone (SA) group (5-year OS, 66.7% vs. 40.9%, P = 0.004; 5-year DFS, 64.1% vs. 36.3%, P = 0.002). CONCLUSIONS: LVI is an independent prognostic risk factor for stage II CRC patients. Combining LVI with the 8th TNM staging system improved the predictive accuracy for CRC prognosis. ACT in stage II CRC patients with LVI+ is beneficial for survival.

Hypoxia­induced circCCDC66 promotes the tumorigenesis of colorectal cancer via the miR­3140/autophagy pathway.

Circular RNAs (circRNAs) have been reported to be involved in the progression of colorectal cancer (CRC). However, the biological role of circCCDC66 in CRC remains unclear. Therefore, the present study aimed to elucidate the mechanisms through which circCCDC66 affects the hypoxia­induced progression of CRC. It was found that hypoxia promoted the progression of CRC and upregulated the expression of circCCDC66. Furthermore, circCCDC66­knockdown reduced viability, migration and invasion, and enhanced the apoptosis of hypoxia­exposed CRC cells. Using the starBase database, it was identified that circCCDC66 may bind to miR­3140. Subsequently, it was confirmed that circCCDC66 serves as a sponge of miR­3140 and the depletion of miR­3140 partly abolished the effects of circCCDC66 on the phenotype of hypoxia­exposed CRC cells. In addition, miR­3140 was validated to inhibit the autophagy pathway. The use of an autophagy inducer partially reversed the miR­3140 overexpression­induced inhibition of the viability and invasion, and the promotion of the apoptosis of hypoxia­exposed CRC cells. In summary, the findings of the present study demonstrated that circCCDC66 facilitates the development of CRC cells under hypoxic conditions via regulation of miR­3140/autophagy. These findings may provide a novel therapeutic option for patients with CRC.

Spontaneous hemopneumothorax after laparoscopy: a case report and literature review.

BACKGROUND: Spontaneous hemopneumothorax (SHP) is defined as the accumulation of >400 mL of blood in the pleural cavity in association with spontaneous pneumothorax. This rare clinical disorder may be life-threatening. CASE PRESENTATION: A 71-year-old woman presented with a 1-month history of recurrent bloody stool, and electronic colonoscopy suggested a rectal mass. Laparoscopic radical resection of rectal cancer was performed. Two days later, she developed chest tightness, shortness of breath, and slight pain in the left chest. Emergency chest radiography revealed mild left pneumothorax and pleural effusion. SHP was suspected and a thoracic drain was inserted. However, the patient developed hemorrhagic shock 3 hours after drainage. She underwent emergency video-assisted thoracic surgery (VATS), which revealed left lung tip rupture with bleeding and adhesive band fracture at the top of the left thoracic cavity. The ruptured lung tissue was removed and electrocoagulation at the adhesion band was performed for hemostasis. The patient was discharged on postoperative day 11. At the time of this writing, she had developed no SHP recurrence or any other complications. CONCLUSIONS: This case shows that conservative treatment may have serious consequences in patients with SHP. Thus, chest X-ray examination and VATS should be performed in patients with SHP.

Programmed death-ligand 1 and survival in colorectal cancers: A meta-analysis.

BACKGROUND: Programmed death-ligand 1 (PD-L1) is a programmed death 1 (PD-1) ligand that plays a pivotal role in the inhibition of the T-cell-mediated immune response. The expression of PD-L1 is associated with the prognosis and clinical outcomes of multiple tumors. However, the prognostic value of PD-L1 overexpression in colorectal cancer is still controversial. In this study, we sought to clarify this by presenting a meta-analysis of relevant studies. METHODS: Databases including PubMed, Web of Science, and EMBASE were systematically searched for studies concerning the expression of PD-L1 and survival in colorectal cancer. The reported hazard ratios (HR) with 95% confidence intervals (CI) of overall survival, disease-free survival, and recurrence-free survival in the included studies were analyzed by fixed effects/random effects models. RESULTS: Fifteen studies involving 3078 patients with colorectal cancer were included in our meta-analysis. Overexpression of PD-L1 was found to be associated with poor overall survival (HR 1.83; 95% CI 1.21, 2.79; P = 0.005) and poor recurrence-free survival (HR 2.78; 95% CI 1.43, 5.42; P = 0.003). However, no correlation was found between PD-L1 overexpression and poor disease-free survival (HR 1.23; 95% CI 0.83, 1.82; P = 0.305). Overexpression of PD-L1 indicating poor survival held true across different geographical areas, sample sizes, analysis types, sources of HRs, and cell types. CONCLUSION: Overexpression of PD-L1 is associated with worse prognosis in patients with colorectal cancer and can guide physicians in the application of PD-1/PD-L1 immune checkpoint-targeted therapy.

High expression of IQGAP3 indicates poor prognosis in colorectal cancer patients.

BACKGROUND: The oncogene IQ motif-containing GTPase activating protein 3 (IQGAP3) is ubiquitously overexpressed in several human cancers. This study was designed to explore the expression and role of IQGAP3 in colorectal cancer. METHODS: We first assessed the IQGAP3 expression level in colorectal cancer. The correlation of IQGAP3 expression with the clinicopathological characteristics and prognosis was then assessed. At last, we investigated the function of IQGAP3 in colorectal cancer by knocking down its expression in colorectal cancer cell lines. RESULTS: Consistent with the conclusions drawn from The Cancer Genome Atlas database, IQGAP3 was upregulated in colorectal cancer at the tissue level and cellular level. Based on immunohistochemistry results of the tissue microarrays, we demonstrated that higher expression of IQGAP3 was associated with higher tumor node metastasis stage (P = 0.005), higher incidence of lymph node metastasis (P = 0.004), and shorter overall survival (P = 0.022). Knockdown of IQGAP3 in colorectal cancer cell lines remarkably decreased their proliferation and migration abilities. CONCLUSION: Our data provide evidence that IQGAP3 significantly promote malignant progression of colorectal cancer and could serve as a potential therapeutic target.

Clinical value of detecting IQGAP3, B7-H4 and cyclooxygenase-2 in the diagnosis and prognostic evaluation of colorectal cancer.

BACKGROUND: The IQ-motif-containing GTPase-activating protein (IQGAP) family comprises three members, IQGAP1, IQGAP2 and IQGAP3. IQGAP3 is the latest addition to the family. This study mainly investigated the novel marker IQGAP3 at serum and tumor tissue levels compared with the markers B7-H4 and cyclooxygenase-2 (COX-2) in patients with colorectal cancer (CRC) and in healthy individuals, aiming to evaluate the diagnostic and prognostic value of IQGAP3 for CRC. MATERIALS AND METHODS: Serum samples were collected prior to any therapy in 118 CRC patients and as part of a routine examination in 85 healthy individuals. Serum IQGAP3, B7-H4 and COX-2 levels were measured using commercially available ELISA kits. Immunohistochemistry was performed to detect the IQGAP3, B7-H4 and COX-2 in tumor tissues and normal para-carcinoma tissues. The receiver operating characteristics (ROC) curve and the area under the curve (AUC) were used to evaluate and compare the diagnostic value of different serum tumor markers. Univariate and multivariate analyses were performed to identify the prognostic risk factors for CRC. RESULTS: IQGAP3, B7-H4 and COX-2 showed low or high expression in tumor tissues while no expression in normal para-carcinoma tissues. Serum levels of IQGAP3 in CRC group were significantly higher than those in healthy control group (P < 0.001). The IQGAP3 AUC was 0.799, while the B7-H4 AUC was 0.795 and the COX-2 AUC was 0.796. IQGAP3 seemed to be superior to B7-H4 and COX-2 in detecting CRC, with the highest sensitivity among the three markers. Multivariate analysis showed that T stage, N stage, differentiation degree, TNM stage and both serum and tissue IQGAP3, B7-H4 and COX-2 levels were significant prognostic factors for CRC. CONCLUSIONS: IQGAP3 has a better diagnostic efficacy than B7-H4 and COX-2 in detecting CRC and it has value in predicting the prognosis of patients with CRC.