The AKT inhibitor AZD5363 elicits synthetic lethality in ARID1A-deficient gastric cancer cells via induction of pyroptosis.

BACKGROUND: Gastric cancer (GC) is a deadly disease with poor overall survival and limited therapeutic options. Genetic alterations such as mutations and/or deletions in chromatin remodeling gene AT-rich interactive domain 1 A (ARID1A) occur frequently in GC. Although ARID1A mutations/deletions are not a druggable target for conventional treatments, novel therapeutic strategies based on a synthetic lethal approach may be effective for the treatment of ARID1A-deficient cancers. METHODS: A kinase inhibitor library containing 551 compounds was screened in ARID1A isogenic GC cells for the ability to induce synthetic lethality effect. Selected hits' activity was validated, and the mechanism of the most potent candidate drug, AKT inhibitor AD5363 (capivasertib), on induction of the synthetic lethality with ARID1A deficiency was investigated. RESULTS: After robust vulnerability screening of 551 diverse protein kinase inhibitors, we identified the AKT inhibitor AZD5363 as being the most potent lead compound in inhibiting viability of ARID1A-/- cells. A synthetic lethality between loss of ARID1A expression and AKT inhibition by AZD5363 was validated in both GC cell model system and xenograft model. Mechanistically, AZD5363 treatment induced pyroptotic cell death in ARID1A-deficient GC cells through activation of the Caspase-3/GSDME pathway. Furthermore, ARID1A occupied the AKT gene promoter and regulated its transcription negatively, thus the GC cells deficient in ARID1A showed increased expression and phosphorylation of AKT. CONCLUSIONS: Our study demonstrates a novel synthetic lethality interaction and unique mechanism between ARID1A loss and AKT inhibition, which may provide a therapeutic and mechanistic rationale for targeted therapy on patients with ARID1A-defective GC who are most likely to be beneficial to AZD5363 treatment.

Accuracy and applicability of the novel pneumoperitoneum three-dimensional volume rendering technique in adhesive small bowel obstruction.

Background: The accurate diagnosis of adhesive small bowel obstruction (ASBO) is challenging for surgeons. The aim of this study was to demonstrate that pneumoperitoneum 3-dimensional volume rendering (3DVR) can provide an accurate diagnosis and has applicability in ASBO. Methods: In this retrospective study, patients who underwent preoperative pneumoperitoneum 3DVR and surgery for ASBO between October 2021 and May 2022 were enrolled. The surgical findings were taken as the gold standard, and the kappa test was used to verify the consistency of the pneumoperitoneum 3DVR results and surgical findings. Results: A total of 22 patients with ASBO were included in this study, 27 sites of obstruction adhesions were found during surgery, and 5 patients had both parietal adhesions and interintestinal adhesions. Sixteen parietal adhesions (16/16) were found using pneumoperitoneum 3DVR (κ=1.00; P<0.001), and the diagnosis of parietal adhesions on pneumoperitoneum 3DVR was perfectly consistent with the surgical findings. Eight (8/11) interintestinal adhesions were found using pneumoperitoneum 3DVR (κ=0.727; P<0.001), and the diagnosis of interintestinal adhesions on pneumoperitoneum 3DVR was substantially consistent with the surgical findings. Conclusions: The novel pneumoperitoneum 3DVR is accurate and applicable in ASBO. It can help personalize the treatment of patients and can be useful in planning a more effective surgical approach.

Transcriptional Regulation of Siglec-15 by ETS-1 and ETS-2 in Hepatocellular Carcinoma Cells.

Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) has been identified as a crucial immune suppressor in human cancers, comparable to programmed cell death 1 ligand (PD-L1). However, the regulatory mechanisms underlying its transcriptional upregulation in human cancers remain largely unknown. Here, we show that the transcription factors ETS-1 and ETS-2 bound to the Siglec-15 promoter to enhance transcription and expression of Siglec-15 in hepatocellular carcinoma (HCC) cells and that transforming growth factor ß-1 (TGF-ß1) upregulated the expression of ETS-1 and ETS-2 and facilitated the binding of ETS-1 and ETS-2 to the Siglec-15 promoter. We further demonstrate that TGF-ß1 activated the Ras/C-Raf/MEK/ERK1/2 signaling pathway, leading to phosphorylation of ETS-1 and ETS-2, which consequently upregulates the transcription and expression of Siglec-15. Our study defines a detailed molecular profile of how Siglec-15 is transcriptionally regulated which may offer significant opportunity for therapeutic intervention on HCC immunotherapy.

The Bioinformatics-Based Analysis Identifies 7 Immune-Related Genes as Prognostic Biomarkers for Colon Cancer.

Colon cancer poses a great threat to human health. Currently, there is no effective treatment for colon cancer due to its complex causative factors. Immunotherapy has now become a new method for tumor treatment. In this study, 487 DEGs were screened from The Cancer Genome Atlas (TCGA) database and ImmPort database, and GeneOntology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was performed. Hierarchical clustering of all samples revealed a significant correlation between colon cancer and immunity. The weighted gene co-expression network analysis (WGCNA) algorithm was used to identify key gene modules associated with immunity in colon cancer, here, module grey60 showed the highest correlation. A protein-protein interaction (PPI) network was constructed using the STRING database to screen hub genes, and subsequently, 7 immune-related genes the most closely associated with colon cancer were identified by differential expression in cancer and paracancer. Finally, a risk prediction model was developed using least absolute shrinkage and selection operator (LASSO) COX analysis, and the accuracy of the model was validated by GSE14333. This study determined that IRF4 and TNFRSF17 were immune-related genes in colon cancer, providing immune-related prognostic biomarkers for colon cancer.

SIK2 represses AKT/GSK3ß/ß-catenin signaling and suppresses gastric cancer by inhibiting autophagic degradation of protein phosphatases.

Salt-inducible kinase 2 (SIK2) is an important regulator in various intracellular signaling pathways related to apoptosis, tumorigenesis and metastasis. However, the involvement of SIK2 in gastric tumorigenesis and the functional linkage with gastric cancer (GC) progression remain to be defined. Here, we report that SIK2 was significantly downregulated in human GC tissues, and reduced SIK2 expression was associated with poor prognosis of patients. Overexpression of SIK2 suppressed the migration and invasion of GC cells, whereas knockdown of SIK2 enhanced cell migratory and invasive capability as well as metastatic potential. These changes in the malignant phenotype resulted from the ability of SIK2 to suppress epithelial-mesenchymal transition via inhibition of AKT/GSK3ß/ß-catenin signaling. The inhibitory effect of SIK2 on AKT/GSK3ß/ß-catenin signaling was mediated primarily through inactivation of AKT, due to its enhanced dephosphorylation by the upregulated protein phosphatases PHLPP2 and PP2A. The upregulation of PHLPP2 and PP2A was attributable to SIK2 phosphorylation and activation of mTORC1, which inhibited autophagic degradation of these two phosphatases. These results suggest that SIK2 acts as a tumor suppressor in GC and may serve as a novel prognostic biomarker and therapeutic target for this tumor.

CircRNA CircRIMS Acts as a MicroRNA Sponge to Promote Gastric Cancer Metastasis.

Circular RNAs (circRNAs), a new category of noncoding RNA, have emerged in recent years as novel biomolecules with important biological functions. Increasing evidence and reports have revealed that circRNAs play an important role in human carcinogenesis and tumor progression. Gastric cancer (GC) is one of the most prevalent life-threatening malignancies worldwide, and in the present study, a novel circRNA molecule (circRIMS) was shown to be associated GC metastasis using next-generation sequencing. CircRIMS remarkably promoted GC cell metastasis in vitro, functioning as a sponge for hsa-miR-148a-5p and hsa-miR-218-5p. In addition, the results of rescue experiments showed that hsa-miR-148a-5p and hsa-miR-218-5p mimics could reverse the tumor-promoting roles of circRIMS in GC. Thus, circRIMS has potential as an early biomarker for use in predicting invasive metastasis in GC and to guide clinical diagnosis and treatment for precision medicine.

Lymphocyte-to-monocyte ratio effectively predicts survival outcome of patients with obstructive colorectal cancer.

BACKGROUND: Obstructive colorectal cancer (OCC) is always accompanied by severe complications, and the optimal strategy for patients with OCC remains undetermined. Different from emergency surgery (ES), self-expandable metal stents (SEMS) as a bridge to surgery (BTS), could increase the likelihood of primary anastomosis. However, the stent failure and related complications might give rise to a high recurrence rate. Few studies have focused on the indications for either method, and the relationship between preoperative inflammation indexes and the prognosis of OCC is still underestimated. AIM: To explore the indications for ES and BTS in OCCs based on preoperative inflammation indexes. METHODS: One hundred and twenty-eight patients who underwent ES or BTS from 2008 to 2015 were enrolled. Receiver operating characteristic (ROC) curve analysis was used to define the optimal preoperative inflammation index and its cutoff point. Kaplan-Meier analyses and Cox proportional hazards models were applied to assess the association between the preoperative inflammation indexes and the survival outcomes [overall survival (OS) and disease-free survival (DFS)]. Stratification analysis was performed to identify the subgroups that would benefit from ES or BTS. RESULTS: OS and DFS were comparable between the ES and BTS groups (P > 0.05). ROC curve analysis showed derived neutrophil-to-lymphocyte ratio (dNLR) as the optimal biomarker for the prediction of DFS in ES (P < 0.05). Lymphocyte-to-monocyte ratio (LMR) was recommended for BTS with regard to OS and DFS (P < 0.05). dNLR was related to stoma construction (P = 0.001), pneumonia (P = 0.054), and DFS (P = 0.009) in ES. LMR was closely related to lymph node invasion (LVI) (P = 0.009), OS (P = 0.020), and DFS (P = 0.046) in the BTS group. dNLR was an independent risk factor for ES in both OS (P = 0.032) and DFS (P = 0.016). LMR affected OS (P = 0.053) and DFS (P = 0.052) in the BTS group. LMR could differentiate the OS between the ES and BTS groups (P < 0.05). CONCLUSION: Preoperative dNLR and LMR could predict OS and DFS in patients undergoing ES and BTS, respectively. For OCC, as the potential benefit group, patients with a low LMR might be preferred for BTS via SEMS insertion.

PI3K/AKT inhibitors aggravate death receptor-mediated hepatocyte apoptosis and liver injury.

The PI3K/AKT signaling pathway is one of the most frequently activated signaling networks in human cancers and has become a valuable target in anticancer therapy. However, accumulating reports suggest that adverse effects such as severe liver injury and inflammation may accompany treatment with pan-PI3K and pan-AKT inhibitors. Our prior work has demonstrated that activation of the PI3K/AKT pathway has a protective role in Fas- or TNFα-induced hepatocytic cell death and liver injury. We postulated that PI3K or AKT inhibitors may exacerbate liver damage via the death factor-mediated hepatocyte apoptosis. In this study we found that several drugs targeting PI3K/AKT either clinically used or in clinical trials sensitized hepatocytes to agonistic anti-Fas antibody- or TNFα-induced apoptosis and significantly shortened the survival of mice in in vivo liver damage models. The PI3K or AKT inhibitors promoted Fas aggregation, inhibited the expression of cellular FLICE-inhibitory protein S and L (FLIPL/S), and enhanced procaspase-8 activation. Conversely, cotreatment with the AKT specific activator SC79 reversed these effects. Taken together, these findings suggest that PI3K or AKT inhibitors may render hepatocytes hypersensitive to Fas- or TNFα-induced apoptosis and liver injury.

AKT activator SC79 protects hepatocytes from TNF-α-mediated apoptosis and alleviates d-Gal/LPS-induced liver injury.

Tumor necrosis factor-α (TNF-α) is a highly pleiotropic cytokine executing biological functions as diverse as cell proliferation, metabolic activation, inflammatory responses, and cell death. TNF-α can induce multiple mechanisms to initiate apoptosis in hepatocytes leading to the subsequent liver injury. Since the phosphoinositide-3-kinase/protein kinase B (PI3K/Akt) pathway is known to have a protective role in death factor-mediated apoptosis, it is our hypothesis that activation of Akt may represent a therapeutic strategy to alleviate TNF-α-induced hepatocyte apoptosis and liver injury. We report here that the Akt activator SC79 protects hepatocytes from TNF-α-induced apoptosis and protects mice from d-galactosamine (d-Gal)/lipopolysaccharide (LPS)-induced TNF-α-mediated liver injury and damage. SC79 not only enhances the nuclear factor-κB (NF-κB) prosurvival signaling in response to TNF-α stimulation, but also increases the expression of cellular FLICE (FADD-like IL-1ß-converting enzyme)-inhibitory protein L and S (FLIPL/S), which consequently inhibits the activation of procaspase-8. Furthermore, pretreatment of the PI3K/Akt inhibitor LY294002 reverses all the SC79-induced hepatoprotective effects. These results strongly indicate that SC79 protects against TNF-α-induced hepatocyte apoptosis and suggests that SC79 is likely a promising therapeutic agent for ameliorating the development of liver injury. NEW & NOTEWORTHY SC79 protects hepatocytes from TNF-α-mediated apoptosis and mice from Gal/LPS-induced liver injury and damage. Cytoprotective effects of SC79 against TNF-α act through both AKT-mediated activation of NF-κB and upregulation of FLIPL/S.

Single-incision laparoscopic appendectomy versus conventional 3-port laparoscopic appendectomy for appendicitis: an updated meta-analysis of randomized controlled trials.

PURPOSE: To compare the efficacy and safety of single-incision laparoscopic appendectomy (SILA) and conventional 3-port laparoscopic appendectomy (3-port LA) for appendectomy. METHODS: We searched the PubMed, Embase, Springer link, and the Cochrane library databases up to April, 2014, for relevant randomized controlled trials (RCTs). Data were pooled by weighted mean differences (WMDs) or odds ratios (ORs) with their 95% confidence intervals (CIs). RESULTS: We found 11 RCTs, with a collective total of 731 patients treated with SILA and 725 patients treated with 3-point LA. Results indicated no significant differences between SILA and 3-port LA in primary outcomes, including wound infection, intra-abdominal abscess, postoperative ileus, and total postoperative complications, and some secondary outcomes, including postoperative pain scores and length of hospital stay. However, SILA was associated with significantly longer operative times (WMD = 6.78, 95% CI = 3.78-9.79, P < 0.00001) and higher doses of analgesia (WMD = 0.96, 95% CI = 0.45-1.47, P = 0.0002) than the 3-port LA. CONCLUSION: Although there was no significant difference in the safety of SILA vs. that of 3-port LA, our findings do not support the application of SILA because of its significantly longer operative times and the higher doses of analgesia required compared with those for 3-point LA.