CCDC68 Maintains Mitotic Checkpoint Activation by Promoting CDC20 Integration into the MCC.

The spindle assembly checkpoint (SAC) ensures chromosome segregation fidelity by manipulating unattached kinetochore-dependent assembly of the mitotic checkpoint complex (MCC). The MCC binds to and inhibits the anaphase promoting complex/cyclosome (APC/C) to postpone mitotic exit. However, the mechanism by which unattached kinetochores mediate MCC formation is not yet fully understood. Here, it is shown that CCDC68 is an outer kinetochore protein that preferentially localizes to unattached kinetochores. Furthermore, CCDC68 interacts with the SAC factor CDC20 to inhibit its autoubiquitination and MCC disassembly. Therefore, CCDC68 restrains APC/C activation to ensure a robust SAC and allow sufficient time for chromosome alignment, thus ensuring chromosomal stability. Hence, the study reveals that CCDC68 is required for CDC20-dependent MCC stabilization to maintain mitotic checkpoint activation.

Prognostic factors for patients with pathologic T1-T2N+ esophageal squamous cell carcinoma: A retrospective study with external validation.

BACKGROUND: Lymph node metastasis is significantly associated with a worse prognosis in patients with localized early-stage esophageal squamous cell carcinoma. This study aimed to explore the prognostic factors and develop a nomogram for predicting survival in patients with pathologic T1-2N+ esophageal squamous cell carcinoma. METHODS: Between 2014 and 2022, patients with pT1-2N+ esophageal squamous cell carcinoma who underwent esophagectomy with lymphadenectomy at 2 institutes were reviewed and assigned to training and external validation cohorts. Independent prognostic factors were identified via univariate and multivariate Cox regression analyses. The nomogram model was developed and evaluated by the area under the receiver operating characteristic curve and calibration curve. RESULTS: In total, 268 patients with a median age of 65 years (range, 40-82) were included and assigned to training (n = 190) and external validation (n = 78) cohorts. The Cox proportional hazards model demonstrated that body mass index (P = .031), surgical approach (P < .001), T stage (P = .015), and Clavien-Dindo classification (P < .001) were independent prognostic factors in the training cohort. The nomogram showed good discrimination, with an area under the receiver operating characteristic curve for 1-year, 3-year, and 5-year of 0.810, 0.789, and 0.809 in the training cohort and 0.782, 0.679, and 0.698 in the validation cohort. The calibration curve showed that the predicted survival probability was in good agreement with the actual survival probability. CONCLUSION: Lower body mass index, left surgical approach, T2 stage, and Clavien-Dindo classification grade III to V were related to worse prognosis in patients with pT1-T2N+ esophageal squamous cell carcinoma. The developed nomogram may predict individual survival accurately.

Endoscopic resection of extra-luminal gastric gastrointestinal stromal tumors using a snare assisted external traction technique (with video).

OBJECTIVE: The primary purpose of the study was to explore the clinical efficacy of the novel snare assisted endoscopic resection of extraluminal growing gastric gastrointestinal stromal tumors (gastric GISTs) using external traction, and the secondary purpose was to compare the novel snare assisted endoscopic resection of extraluminal GISTs with the standard laparoscopic procedure. METHODS: We retrospectively analyzed the patients who underwent novel external traction assisted endoscopic resection or laparoscopic resection for their extraluminal gastric GIST ≤5 cm in diameter. RESULTS: A total of 111 patients (27 in the endoscopic group and 84 in the laparoscopic group) were included in this study. There was no significant difference in tumor diameter and complication rate between the two groups. The overall procedure time was slightly higher in the endoscopic group compared to the laparoscopic group (P = 0.034). However, postoperative hospitalization time (P < 0.001) and postoperative fasting time (P = 0.005) were shorter in the endoscopic group compared to the laparoscopic group. CONCLUSION: Snare external traction-assisted endoscopic resection of extraluminal growing gastric GISTs is safe and effective, and it provides a new adjunctive method for endoscopic resection of GIST.

Genomic context- and H2AK119 ubiquitination-dependent inheritance of human Polycomb silencing.

Polycomb repressive complexes 1 and 2 (PRC1 and 2) are required for heritable repression of developmental genes. The cis- and trans-acting factors that contribute to epigenetic inheritance of mammalian Polycomb repression are not fully understood. Here, we show that, in human cells, ectopically induced Polycomb silencing at initially active developmental genes, but not near ubiquitously expressed housekeeping genes, is inherited for many cell divisions. Unexpectedly, silencing is heritable in cells with mutations in the H3K27me3 binding pocket of the Embryonic Ectoderm Development (EED) subunit of PRC2, which are known to disrupt H3K27me3 recognition and lead to loss of H3K27me3. This mode of inheritance is less stable and requires intact PRC2 and recognition of H2AK119ub1 by PRC1. Our findings suggest that maintenance of Polycomb silencing is sensitive to local genomic context and can be mediated by PRC1-dependent H2AK119ub1 and PRC2 independently of H3K27me3 recognition.

Ultrasound-based radiomics machine learning models for diagnosing cervical lymph node metastasis in patients with non-small cell lung cancer: a multicentre study.

BACKGROUND: Cervical lymph node metastasis (LNM) is an important prognostic factor for patients with non-small cell lung cancer (NSCLC). We aimed to develop and validate machine learning models that use ultrasound radiomic and descriptive semantic features to diagnose cervical LNM in patients with NSCLC. METHODS: This study included NSCLC patients who underwent neck ultrasound examination followed by cervical lymph node (LN) biopsy between January 2019 and January 2022 from three institutes. Radiomic features were extracted from the ultrasound images at the maximum cross-sectional areas of cervical LNs. Logistic regression (LR) and random forest (RF) models were developed. Model performance was assessed by the area under the curve (AUC) and accuracy, validated internally and externally by fivefold cross-validation and hold-out method, respectively. RESULTS: In total, 313 patients with a median age of 64 years were included, and 276 (88.18%) had cervical LNM. Three descriptive semantic features, including long diameter, shape, and corticomedullary boundary, were selected by multivariate analysis. Out of the 474 identified radiomic features, 9 were determined to fit the LR model, while 15 fit the RF model. The average AUCs of the semantic and radiomics models were 0.876 (range: 0.781-0.961) and 0.883 (range: 0.798-0.966), respectively. However, the average AUC was higher for the semantic-radiomics combined LR model (0.901; range: 0.862-0.927). When the RF algorithm was applied, the average AUCs of the radiomics and semantic-radiomics combined models were improved to 0.908 (range: 0.837-0.966) and 0.922 (range: 0.872-0.982), respectively. The models tested by the hold-out method had similar results, with the semantic-radiomics combined RF model achieving the highest AUC value of 0.901 (95% CI, 0.886-0.968). CONCLUSIONS: The ultrasound radiomic models showed potential for accurately diagnosing cervical LNM in patients with NSCLC when integrated with descriptive semantic features. The RF model outperformed the conventional LR model in diagnosing cervical LNM in NSCLC patients.

Advances and challenges of first-line immunotherapy for non-small cell lung cancer: A review.

The current use of immune checkpoint inhibitors (ICIs) for the treatment of lung cancer has dramatically changed the clinical strategy for metastatic non-small cell lung cancer (mNSCLC). As a result of great achievements in clinical trials, 6 programmed death-1 inhibitors (sintilimab, camrelizumab, tislelizumab, pembrolizumab, cemiplimab, and nivolumab), 2 programmed death-ligand 1 inhibitors (sugemalimab and atezolizumab), and 1 cytotoxic T lymphocyte-associated antigen-4 inhibitor (ipilimumab) have been approved as first-line treatment for mNSCLC by the US Food and Drug Administration. Recently, research on ICIs has shifted from a large number of second-line to first-line settings in clinical trials. Results from first-line trials have shown that almost all driver-negative mNSCLC are treated with ICIs and significantly prolong patient survival; however, the low response rate and adverse reactions to immunotherapy remain to be addressed. Here, we summarize the use of ICIs, including monotherapy and combination therapy, in the first-line treatment of mNSCLC in recent years and discuss the low response rate and adverse reactions of ICIs as well as the challenges and expectations for the first-line treatment of mNSCLC in the future.

LncRNAs in non-small cell lung cancer: novel diagnostic and prognostic biomarkers.

Non-small cell lung cancer (NSCLC) is one of the main causes of cancer-related death worldwide, with a serious impact on human health and life. The identification of NSCLC at an early stage is a formidable task that frequently culminates in a belated diagnosis. LncRNA is a kind of noncoding RNA with limited protein-coding capacity, and its expression is out of balance in many cancers, especially NSCLC. A large number of studies have reported that lncRNA acts a vital role in regulating angiogenesis, invasion, metastasis, and the proliferation and apoptosis of tumor cells, affecting the occurrence and development of NSCLC. Abundant evidence demonstrates that lncRNAs may serve as potential biomarkers for NSCLC diagnosis and prognosis. In this review, we summarize the latest progress in characterizing the functional mechanism of lncRNAs involved in the development of NSCLC and further discuss the role of lncRNAs in NSCLC therapy and chemotherapy resistance. We also discuss the advantages, limitations, and challenges of using lncRNAs as diagnostic or prognostic biomarkers in the management of NSCLC.