Negative correlation between acetyl-CoA acyltransferase 2 and cetuximab resistance in colorectal cancer.

The emergence of anti-EGFR therapy has revolutionized the treatment of colorectal cancer (CRC). However, not all patients respond consistently well. Therefore, it is imperative to conduct further research to identify the molecular mechanisms underlying the development of cetuximab resistance in CRC. In this study, we find that the expressions of many metabolism-related genes are downregulated in cetuximab-resistant CRC cells compared to their sensitive counterparts. Specifically, acetyl-CoA acyltransferase 2 (ACAA2), a key enzyme in fatty acid metabolism, is downregulated during the development of cetuximab resistance. Silencing of ACAA2 promotes proliferation and increases cetuximab tolerance in CRC cells, while overexpression of ACAA2 exerts the opposite effect. RTK-Kras signaling might contribute to the downregulation of ACAA2 expression in CRC, and ACAA2 predicts CRC prognosis in patients with Kras mutations. Collectively, our data suggest that modulating ACAA2 expression contributes to secondary cetuximab resistance in Kras wild-type CRC patients. ACAA2 expression is related to Kras mutation and demonstrates a prognostic role in CRC patients with Kras mutation. Thus, ACAA2 is a potential target in CRC with Kras mutation.

JUNB mediates oxaliplatin resistance via the MAPK signaling pathway in gastric cancer by chromatin accessibility and transcriptomic analysis.

Currently, platinum-containing regimens are the most commonly used regimens for advanced gastric cancer patients, and chemotherapy resistance is one of the main reasons for treatment failure. Thus, it is important to reveal the mechanism of oxaliplatin resistance and to seek effective intervention strategies to improve chemotherapy sensitivity, thereby improving the survival and prognosis of gastric cancer patients. To understand the molecular mechanisms of oxaliplatin resistance, we generate an oxaliplatin-resistant gastric cancer cell line and conduct assay for transposase-accessible chromatin sequencing (ATAC-seq) and RNA sequencing (RNA-seq) for both parental and oxaliplatin-resistant AGS cells. A total of 3232 genomic regions are identified to have higher accessibility in oxaliplatin-resistant cells, and DNA-binding motif analysis identifies JUNB as the core transcription factor in the regulatory network. JUNB is overexpressed in oxaliplatin-resistant gastric cancer cells, and its upregulation is associated with poor prognosis in gastric cancer patients, which is validated by our tissue microarray data. Moreover, chromatin immunoprecipitation sequencing (ChIP-seq) analysis reveals that JUNB binds to the transcriptional start site of key genes involved in the MAPK signaling pathway. Knockdown of JUNB inhibits the MAPK signaling pathway and restores sensitivity to oxaliplatin. Combined treatment with the ERK inhibitor piperlongumine or MEK inhibitor trametinib effectively overcomes oxaliplatin resistance. This study provides evidence that JUNB mediates oxaliplatin resistance in gastric cancer by activating the MAPK pathway. The combination of MAPK inhibitors with oxaliplatin overcomes resistance to oxaliplatin, providing a promising treatment opportunity for oxaliplatin-resistant gastric cancer patients.

Establishment of a mouse model for ovarian cancer-associated venous thromboembolism.

Patients with ovarian cancer are at increased risk of venous thromboembolism (VTE), and the cumulative incidence is high, particularly at advanced stages of this disease. Nevertheless, it is challenging to investigate the molecular mechanisms of ovarian cancer-associated VTE (OC-VTE), mainly due to the lack of a well-developed animal model for this disease. We generated a mouse model for developing OC-VTE using ovarian cancer cell injection in combination with the inferior vena cava stenosis method. The rate of thrombosis in the OC-VTE group was 50%, compared with 0 in the control group. Moreover, we conducted a proteomic analysis using platelets from these models and revealed differentially expressed proteins between the OC-VTE and control groups, including upregulated and downregulated proteins. Gene Ontology analysis revealed that these differentially expressed proteins were mostly enriched in the biological process of negative regulation of fibrinolysis and the cellular component of the fibrinogen complex, both of which play key roles in thrombosis. In conclusion, this study lays the foundation for further investigation of the underlying mechanisms of how ovarian cancer promotes VTE formation.

Surgical and oncological outcomes of an improved nerve-sparing radical hysterectomy technique: 6 years of experience at two centres.

OBJECTIVE: An improved nerve-sparing radical hysterectomy (NSRH), which is based on the paravesico-vaginal space, has been recently introduced in a phase II, prospective clinical trial by our team. This study aims to report the surgical and oncological outcomes of this improved NSRH. METHODS: One hundred seventy-seven consecutive patients were enrolled in our study and underwent the improved NSRH. The proportion of successful catheter removal and postvoid residual urine volume (PVR) of 50 mL or less at postoperative day 7 or day 4 was used to assess surgical outcomes. The local control rate (LCR), disease free survival (DFS), and overall survival (OS) were used to assess oncological outcomes. RESULTS: Postoperative 30-day complications occurred in 27/177 (15.3%) patients. The rate of successful catheter removal and PVR of 50 mL or less were 85.2% (23/27) and 66.7% (18/27) at postoperative day 7, and 73.3% (110/150) and 35.3% (53/150) at postoperative day 4. A total of 13 (7.9%) patients showed recurrence after a median follow-up time of 39.2 months (range 3.2-68.1 months). The estimated 2-year and 5-year DFS rates were 92.2% and 91.1%, respectively. Seven (4.2%) patients presented local recurrence, and five (3.0%) patients were dead at the end of the follow-up period. The estimated 5-year LCR and OS were 95.1% and 96.2%, respectively. In univariate analysis, International Federation of Gynecology and Obstetrics (FIGO) stage, lymphovascular space invasion (LVSI), and lymph node metastasis were found to be the prognostic risk factors of DFS. Patients with LVSI were associated with a worse DFS according to the multivariate analysis. CONCLUSIONS: The improved NSRH in our study may provide better surgical outcomes without compromising the survival in patients with early cervical cancer.

An improved nerve-sparing radical hysterectomy technique for cervical cancer using the paravesico-vaginal space as a new surgical landmark.

Bladder dysfunction remains a major postoperative challenge for early stage cervical cancer patients. The present prospective phase 2 trial in patients with stage IB1 and IIA1 cervical cancer follows up on our previous, unpublished work describing a new surgical landmark, the paravesico-vaginal space. We describe a novel nerve-sparing radical hysterectomy (NSRH) approach to treat early stage cervical cancer without compromising local control rate or survival. Between September 2015 and August 2016, 49 patients were enrolled to receive NSRH. The bladder catheter was routinely removed on postoperative day 4. The primary endpoints were rate of postvoid residual urine volume (PVR) ≤ 50 ml and proportion of patients with successful catheter removal (ClinicalTrials.gov Identifier: NCT02562729). Anatomically, from ventral to dorsal, the terminal ureter, deep uterine vein, and cardinal ligament were the three markers of the paravesico-vaginal space. The median operative time was 100 min, and the median blood loss was 200 ml. Thirty-four patients (69.4%) had successful catheter removal on postoperative day 4, and 17 patients (34.7%) had a PVR ≤ 50 ml. Our results suggest that by accessing the paravesico-vaginal space landmark, the bladder branch of the inferior hypogastric plexus can be completely preserved, contributing to greater NSRH efficiency without compromising outcomes for patients with early stage cervical cancer.