Plasma ctDNA enhances the tissue-based detection of oncodriver mutations in colorectal cancer.

PURPOSE: The advent of circulating tumor DNA (ctDNA) technology has provided a convenient and noninvasive means to continuously monitor cancer genomic data, facilitating personalized cancer treatment. This study aimed to evaluate the supplementary benefits of plasma ctDNA alongside traditional tissue-based next-generation sequencing (NGS) in identifying targetable mutations and tumor mutational burden (TMB) in colorectal cancers (CRC). METHODS: Our study involved 76 CRC patients, collecting both tissue and plasma samples for NGS. We assessed the concordance of gene mutational status between ctDNA and tissue, focusing on actionable genes such as KRAS, NRAS, PIK3CA, BRAF, and ERBB2. Logistic regression analysis was used to explore variables associated with discordance and positive mutation rates. RESULTS: In total, 26 cancer-related genes were identified. The most common variants in tumor tissues and plasma samples were in APC (57.9% vs 19.7%), TP53 (55.3% vs 22.4%) and KRAS (47.4% vs 43.4%). Tissue and ctDNA showed an overall concordance of 73.53% in detecting actionable gene mutations. Notably, plasma ctDNA improved detection for certain genes and gene pools. Variables significantly associated with discordance included gender and peritoneal metastases. TMB analysis revealed a higher detection rate in tissues compared to plasma, but combining both increased detection. CONCLUSIONS: Our study highlights the importance of analyzing both tissue and plasma for detecting actionable mutations in CRC, with plasma ctDNA offering added value. Discordance is associated with gender and peritoneal metastases, and TMB analysis can benefit from a combination of tissue and plasma data. This approach provides valuable insights for personalized CRC treatment.

UBXN11 Predicts as a Poor Index for Colorectal Cancer and Contributes to the Tumorigenesis by Activating NF-κB Signaling.

BACKGROUND: The complex mechanisms of colorectal cancer (CRC) pathogenesis and progression remain poorly understood. This study endeavors to unravel the role of UBXN11within the context of CRC. METHODS: UBXN11 expression level in CRC, stomach adenocarcinoma and esophageal carcinoma, and the overall survival in corresponding cancers were analyzed using UALCAN database. Human CRC cell lines and xenograft mouse model with UBXN11 overexpression were established to investigate the pathological role of UBXN11 in CRC progression. Luciferase assay, qPCR, and Western blot were performed to dissect the interaction between UBXN11 and NF-κB signaling. RESULTS: Heightened UBXN11 expression was observed in various digestive tract tumors, which was positively correlated with the reduced overall survival rates in CRC patients. Overexpression of UBXN11 significantly enhanced CRC cell proliferation in vitro and promoted tumor growth in vivo. Mechanistically, UBXN11 promoted CRC tumorigenesis through increasing the activation of NF-κB signaling pathway. CONCLUSIONS: This study underscores the pivotal role of UBXN11 in CRC progression and paves the way for novel therapeutic strategies for CRC treatment.

The coumarin component isofraxidin targets the G-protein-coupled receptor S1PR1 to modulate IL-17 signaling and alleviate ulcerative colitis.

OBJECTIVE: The increasing global prevalence of ulcerative colitis (UC) underscores the imperative to explore novel therapeutic approaches. Traditional Chinese medicine has historically shown potential in addressing this ailment. The current study aimed to elucidate the functional attributes and underlying mechanisms of isofraxidin, a coumarin derivative from Acanthopanax, in the context of UC. METHODS: A murine model of dextran sodium sulfate (DSS)-induced UC was established, and we conducted a comprehensive assessment of the influence of isofraxidin on UC symptomatology, colonic histopathological manifestations, the inflammatory response, and apoptosis. The potential receptor of isofraxidin was initially identified through the Target database and molecular docking analysis. Subsequent in vivo and in vitro experiments were conducted to determine the effects of isofraxidin on the identified receptor and associated signaling pathways. Transfection was used to examine the receptor's role in the regulatory mechanism of isofraxidin. RESULTS: Isofraxidin reduced UC symptoms and colonic histopathological impairments. Furthermore, isofraxidin ameliorated the DSS-induced inflammatory response and apoptosis in tissues. S1PR1 was identified as a target of isofraxidin and effectively suppressed activation of the IL-17 signaling pathway. Intriguingly, cellular experiments indicated that overexpression of S1PR1 counteracted the protective effect of isofraxidin. DISCUSSION: In summary, our investigation revealed that isofraxidin could modulate S1PR1 and regulate the IL-17 signaling pathway, thus ameliorating DSS-induced UC. These findings establish a robust foundation for considering isofraxidin as a prospective therapeutic intervention to treat UC.

DR6 Augments Colorectal Cancer Cell Growth, Invasion, and Stemness by Activating AKT/NF-κB Pathway.

This study aims to elucidate the role and mechanisms of Death Receptor 6 (DR6), a member of the tumor necrosis factor receptor superfamily, in the malignant progression of colorectal cancer (CRC). The association of DR6 expression levels and CRC patient survival was examined using the CRC cohort data from GEPIA database. The functional role of DR6 in CRC cells was investigated by performing loss-of-function and gain-of-function experiments based on CCK-8 proliferation assay, transwell migration and invasion assay, and sphere-forming assays. Xenograft model of CRC cells in nude mouse was established to evaluate the impact of DR6 knockdown on CRC tumorigenesis. Elevated expression of DR6 was correlated with an unfavorable prognosis in CRC patients. In vitro functional assays demonstrated that silencing DR6 considerably suppressed the proliferation, migration, invasion, and stemness of CRC cells, whereas its overexpression showed an opposite effect. DR6 knockdown also attenuated tumor formation of CRC cells in the nude mice. Mechanistically, silencing DR6 reduced the phosphorylation of AKT and NF-κB in CRC cells, and the treatment with an AKT activator (SC79) abrogated the inhibitory effects of DR6 knockdown on the malignant features of CRC cells. Our data suggest that DR6 contributes to the malignant progression of CRC by activating AKT/NF-κB pathway, indicating its clinical potential as a prognostic marker and therapeutic target for CRC.

Towards Semi-Autonomous Colon Screening Using an Electromagnetically Actuated Soft-Tethered Colonoscope Based on Visual Servo Control.

OBJECTIVE: Conventional colonoscopy using a flexible colonoscope remains two major limitations, including patient discomfort and difficult manipulations for surgeons. Robotic colonoscopes have been developed to conduct colonoscopy in a patient-friendly manner. However, most robotic colonoscopes still maintain nonintuitive and difficult manipulations, which limits their clinical applications. In this paper, we demonstrated visual servo-based semi-autonomous manipulations of an electromagnetic actuated soft-tethered (EAST) colonoscope, which aims to lower difficulties of robotic colonoscope manipulations. METHODS: Kinematic modeling of EAST colonoscope is conducted, with an adaptive visual servo controller established. Template matching method and a lumen and polyp detection model are developed to enable semi-autonomous manipulations, including region-of-interest automatic tracking and autonomous navigation with automatic polyp detection. RESULTS: The EAST colonoscope demonstrates visual servoing with an average convergence time of around 2.5 s and performs disturbance rejection within 3.0 s. Semi-autonomous manipulations were conducted in both a commercialized colonoscopy simulator and an ex-vivo porcine colon to show the efficacy of reducing the user workload compared to manual control. CONCLUSION: The EAST colonoscope can perform visual servoing and semi-autonomous manipulations with the developed methods in both laboratory and ex-vivo environments. SIGNIFICANCE: The proposed solutions and techniques improve the autonomy level of robotic colonoscopes and reduce user workloads, which promotes the development and clinical translation of robotic colonoscopy.

A Semi-Autonomous Stereotactic Brain Biopsy Robotic System With Enhanced Surgical Safety and Surgeon-Robot Collaboration.

OBJECTIVE: Despite benefits brought by recent neurosurgical robots, surgical safety and surgeon-robot collaboration remain significant challenges. In this article, we analyze and address these problems in the context of brain biopsy, by proposing a semi-autonomous system. METHODS: A robotic module is designed for the automation of all the brain biopsy procedures, and a biopsy cannula with tissue blocker is developed to avoid tissue excess and haemorrhage. In addition, two methods are proposed for surgical safety and surgeon-robot collaboration enhancement. First, a priority-based control framework is proposed for neuronavigation with simultaneous optical tracking line-of-sight maintenance and surgeon avoidance. Second, after neuronavigation, an adaptive reconfiguration method is developed to optimize the arm angle of KUKA robot based on the surgeon's pose, for workspace interference minimization, high robot dexterity, and joint-limit avoidance. RESULT: Effectiveness of the proposed solution demonstrated by simulations and experiments. CONCLUSION: The system can perform automatic navigation with simultaneous optical tracking maintenance and surgeon avoidance, autonomous brain biopsy, and adaptive reconfiguration for workspace interference minimization. SIGNIFICANCE: This work improves existing neurosurgical systems, in terms of autonomy level from mechanical guidance to task autonomy, surgical safety, and surgeon-robot collaboration.

Ascending colon metastasis after breast cancer surgery: a case report and literature review.

Background: Breast cancer is the most common cancer in women. The tumor is prone to metastasize in the brain, lung, liver, bone, and other organs; however, generally, it is less likely to metastasize in the digestive tract. Thus, breast cancer metastasizes to colon is rarely happened and easily ignored by clinicians. Such misdiagnosis may lead to delay the further diagnosis and treatment of patients, or even cause the life danger of patients due to the progress of the disease. Therefore, we propose such case reports to arouse clinicians' attention to the rare case of digestive tract metastasis after treatment of breast cancer. We also conducted a retrospective analysis of the relevant case reports. We suggest that because breast cancer with gastrointestinal metastasis rarely occurs, and because of the lack of specificity of syndromes, it is easily misdiagnosed. Thus, the attention of the receiving doctor needs to be drawn to this tumor. We also summarized the specificity and sensitivity of the commonly used immunohistochemical detection indicators of digestive tract metastasis of breast cancer. Case Description: We presented a 67-year-old female went to hospital because of "acute pain in the right lower abdomen", after computed tomography (CT) examination, the patient was diagnosed as "acute appendicitis" and underwent laparoscopic appendectomy (LA), the post-surgery pathology confirmed metastatic carcinoma to the appendix from the breast that was removed 10 years early. The patient first came to our hospital 10 years ago because of the right breast malignant tumor. After modified radical mastectomy for right breast cancer, the patient underwent chemotherapy for 6 cycles. Tamoxifen endocrine therapy was administered after chemotherapy. The patient had a regular follow-up, with no signs of distant metastasis and local recurrence. Conclusions: Metastasis from breast cancer to the gastrointestinal tract is extremely rare. For patients with breast cancer, endoscopy should be adopted as a routine follow-up item. For suspicious lesions found under endoscopy, immunohistochemistry stain should be adopted to ensure the diagnosis. For lesions that are confirmed to be metastatic from breast cancer, proper treatment should be carried out based on patients' condition to improve the prognosis.

IGHG1 upregulation promoted gastric cancer malignancy via AKT/GSK-3ß/ß-Catenin pathway.

BACKGROUND: Despite current advances in gastric cancer treatment, disease metastasis and chemo-resistance remain as major hurdles against better overall prognosis. Previous studies indicated that IGHG1 as well as -Catenin serve as important regulators of tumor cellular malignancy. Therefore, understanding detailed molecular mechanism and identifying druggable target will be of great potentials in future therapeutic development. METHODS: Surgical tissues and gastric cancer cell lines were retrieved to evaluate IGHG1 expression for patients with or without lymph node/distal organ metastasis. Functional assays including CCK8 assay, Edu assay, sphere formation assay and transwell assay, wound healing assay, etc. were subsequently performed to evaluate the impact of IGHG1/-catenin axis on tumor cell proliferation, migration and chemo-resistance. RESULTS: Gastric cancer tissues and tumor cell lines demonstrated significantly higher level of IGHG1. Functional study further demonstrated that IGHG1 promoted proliferative and migration as well as chemo-resistance of gastric cancer tumor cells. Further experiments indicated that IGHG1 activated AKT/GSK-3/-Catenin axis, which played crucial role in regulation of proliferative and chemo-resistance of gastric cancer cells. CONCLUSION: This study provided novel evidences that IGHG1 acted as oncogene by promotion of gastric cancer cellular proliferation, migration and chemo-resistance. Our research further suggested that IGHG1/AKT/GSK-3ß/ß-Catenin axis acted as novel pathway which regulated gastric cancer cellular malignant behavior. Our research might inspire future therapy development to promote overall prognosis of gastric cancer patients.

Microsatellite instability in Chinese gastric cancer and its correlation with clinical characteristics.

BACKGROUND: Microsatellite instability (MSI) remains a focus of interest in cancer research, but the characteristics of MSI in gastric cancer (GC) are ambiguous. METHODS: In this retrospective study, we analyzed the prevalence of MSI and the expression of programmed death-ligand 1 (PD-L1) and cluster of differentiation 8 (CD8) cells in Chinese GC patients. A total of 393 GC patients admitted to two centers from January 2010 to December 2017 were enrolled. RESULTS: The prevalence of MSI in this cohort was 3.4% and most frequently occurred in females, patients aged between 59 and 69 years, and patients at a lower clinical stage. All MSI GCs had CD8 expression but lacked PD-L1 expression, indicating that MSI was related to CD8 expression but irrelevant to PD-L1 expression. However, there was no significant difference in the expression of CD8/PD-L1 between MSI GC and microsatellite stable (MSS) GC. Kaplan-Meier survival curves revealed that patients with MSI had a significantly longer overall survival (OS) than patients with MSS. CONCLUSIONS: In Chinese GC patients, MSI frequently occurred in females, patients aged between 59 and 69, and patients with lower clinical stages. Patients with MSI-High (MSI-H) and MSI-Low (MSI-L) had a longer OS than patients with MSS. MSI was related to CD8 expression but irrelevant to PD-L1 expression.

Ginsenoside Rg3 enhances the anticancer effect of 5­FU in colon cancer cells via the PI3K/AKT pathway.

Chemotherapy is one of the most commonly used treatments for patients with advanced colon cancer, yet the toxicity of chemotherapy agents, such as 5­fluorouracil (5­FU), limits the effectiveness of chemotherapy. Ginsenoside Rg3 (Rg3) is an active ingredient isolated from ginseng. Rg3 has been shown to display anticancer effects on a variety of malignancies. Yet, whether Rg3 synergizes the effect of 5­FU to inhibit the growth of human colon cancer remains unknown. The present study was designed to ascertain whether Rg3 is able to enhance the anti­colon cancer effect of 5­FU. The results revealed that combined treatment of Rg3 and 5­FU significantly enhanced the inhibition of the proliferation, colony formation, invasion and migration of human colon cancer cells (SW620 and LOVO) in vitro. We also found that combined treatment of Rg3 and 5­FU significantly enhanced the apoptosis of colon cancer cells by activating the Apaf1/caspase 9/caspase 3 pathway and arrested the cell cycle of the colon cancer cells in G0/G1 by promoting the expression of Cyclin D1, CDK2 and CDK4. In addition, the PI3K/AKT signaling pathway in colon cancer cells was suppressed by Rg3 and 5­FU. In vivo, Rg3 synergized the effect of 5­FU to inhibit the growth of human colon cancer xenografts in nude mice. Similarly, combined treatment of Rg3 and 5­FU altered the expression of colon cancer protein in vivo and in vitro. Collectively, the present study demonstrated that ginsenoside Rg3 enhances the anticancer effect of 5­FU in colon cancer cells via the PI3K/AKT pathway.

THBS4 predicts poor outcomes and promotes proliferation and metastasis in gastric cancer.

Gastric cancer (GC), a common and lethal cancer in the world, has a high risk of metastasis. Our study was to explore the effects of THBS4 on GC progress and metastasis and the underlying mechanisms. The proliferations of MGC-803 and BGC-823 cells were analyzed via cell count, MTT, and soft agar colony formation assay. The migration and invasion of transfected GC cells was investigated via transwell migration and invasion assay. The mRNA abundance of THBS4 and KLF9 was detected by quantitative real-time PCR (qPCR). The analysis of Gene Expression Omnibus (GEO) dataset (GSE26253) suggested that THBS4 was up-regulated in recurrent GC patients and was positively correlated with the increase in pathological stage and poor prognosis in GC. THBS4 stimulated the proliferations of GC cells. Moreover, THBS4 overexpression fostered the migration and invasion of GC cells. Further, the bioinformatics analysis of the cancer genome atlas dataset suggested that there may be a positive correlation between THBS4 and KLF9 expression. QPCR analysis proved that transfected with THBS4 overexpression plasmid enhanced KLF9 expression in GC cells. THBS4 mRNA and protein expression were up-regulated in MGC-803 and BGC-823 cells compared to those in non-tumoral gastric cells. KLF9 overexpression significantly stimulated the proliferation and metastasis of MGC-803 and BGC-823 cells. Besides, KLF9 siRNA inhibited the enhanced viability, migration, and invasion of MGC-803 cells caused by the transfection with THBS4 overexpression plasmid. In conclusion, THBS4 had positive effects on GC proliferation and metastasis via targeting KLF9.