CRISPRing KRAS: A Winding Road with a Bright Future in Basic and Translational Cancer Research.

Once considered "undruggable" due to the strong affinity of RAS proteins for GTP and the structural lack of a hydrophobic "pocket" for drug binding, the development of proprietary therapies for KRAS-mutant tumors has long been a challenging area of research. CRISPR technology, the most successful gene-editing tool to date, is increasingly being utilized in cancer research. Here, we provide a comprehensive review of the application of the CRISPR system in basic and translational research in KRAS-mutant cancer, summarizing recent advances in the mechanistic understanding of KRAS biology and the underlying principles of drug resistance, anti-tumor immunity, epigenetic regulatory networks, and synthetic lethality co-opted by mutant KRAS.

Comparison of indocyanine green-near-infrared fluorescence guided and traditional mediastinal lymphadenectomy during radical esophagectomy: A randomized controlled trial.

BACKGROUND: The extent of lymph node dissection during radical esophagectomy remains a controversial topic. Thus, this study mainly aimed to explore the location of sentinel lymph nodes in esophageal squamous cell carcinoma and the application value of the indocyanine green-near-infrared fluorescence system in lymphadenectomy. METHODS: This randomized controlled clinical trial (ClinicalTrials.gov, NCT04615806) included 42 participants without neoadjuvant therapy who were lymph node negative based on positron emission tomography/computed tomography findings. Traditional esophagectomy with indocyanine green-near-infrared fluorescence imaging was performed after injecting 0.5 mL indocyanine green (1.25 mg/mL) into the esophageal submucosa in the 4 peritumoral quadrants. The primary endpoint was to determine the location of the sentinel lymph node in esophageal squamous cell carcinoma based on postoperative pathologic reports. RESULTS: A total of 40 patients, with 20 in each group, were included in the final analysis. In the indocyanine green group, indocyanine green-near-infrared fluorescence imaging was successful in all subjects. Seven cases (cases 2, 3, 9, 11, 17, 18, and 20) in the indocyanine green group exhibited lymph node metastases, all of which were near-infrared positive. The detection rate, positive predictive value, negative predictive value, sensitivity, and specificity were 100% (20 of 20 cases), 8.7% (13/150), 100% (265/265), 100% (13/13), and 65.9% (265/402), respectively. All near-infrared-negative lymph nodes were nonmetastatic lymph nodes. In addition, the number of mediastinal lymph nodes resected in the indocyanine green group was significantly higher than in the non-indocyanine green group. CONCLUSION: Indocyanine green-near-infrared might be an important and promising technique in predicting sentinel lymph nodes of esophageal squamous cell carcinoma and could significantly improve the detection rate of lymph nodes of esophageal squamous cell carcinoma.

miR-1301-3p promotes invasion and migration and EMT progression in esophageal cancer by downregulating NBL1 expression.

BACKGROUND: Esophageal cancer (ESCA) is one of the most aggressive and lethal human malignant cancers. MicroRNA-1301-3p (miR-1301-3p) plays vital roles in a majority of malignancies. The aim of this study was to investigate the role of miR-1301-3p/NBL1 axis on ESCA cell invasion, migration, epithelial-mesenchymal transition (EMT) process, as well as its association with prognosis of ESCA patients. METHODS: The expression levels of miR-1301-3p and NBL1 were predicted by bioinformatics and further verified by RT-qPCR assays. Kaplan-Meier (K-M) plotter analysis and univariate and multivariate Cox analyses were used to evaluate the relationship between miR-1301-3p and clinicopathological variables and prognosis. The role of miR-1301-3p on cell invasion, migration was detected by transwell invasion, and wound healing assays, respectively. The EMT-related proteins were detected by western blot. The target genes and the target binding sites were predicted by bioinformatics and further determined by RT-qPCR assay. RESULTS: MiR-1301-3p was remarkably upregulated in ESCA tissues and cells, and its high expression was associated with poor prognosis of ESCA. Overexpression of miR-1301-3p promoted ESCA cell invasion, migration and mediated EMT process in vitro, whereas knockdown of miR-1301-3p showed the opposite effects. Moreover, NBL1 was predicted as a target gene of miR-1301-3p. NBL1 was lowly expressed in ESCA cells and significantly decreased after upregulation of miR-1301-3p. Meanwhile, we found that low expression of NBL1 was significantly associated with poor prognosis of ESCA patients. CONCLUSION: MiR-1301-3p is a potential biomarker for predicting the prognosis of ESCA patients. It may promote ESCA invasion, migration and EMT progression by regulating NBL1 expression.

Cost-effectiveness of osimertinib versus placebo in resected EGFR-mutated non-small cell lung cancer in China.

PURPOSE: We aim to assess whether osimertinib postoperative adjuvant therapy, compared with placebo, is cost-effective in China. METHODS: We set up the Markov model that contains three health states over a 20-year period. Data were collected from the ADAURA trial that included transition probabilities and safety data. Through the analysis of literature and local charges, we explore both the cost and utility values. Sensitivity analyses were employed using TreeAge Pro software to access model stability. FINDINGS: Patients in the osimertinib group had 1.46 more Quality-adjusted Life Years (8.45 QALYs vs 6.99 QALYs) than the placebo group at an incremental cost of $14098.51($39962.99 vs $25864.48). Compared with the placebo group, the treatment strategy with osimertinib postoperative adjuvant therapy had an incremental cost-effectiveness ratio of $9661.97/QALY. The probability of the osimertinib-assisted therapy strategy being cost-effective will reach 100% if the threshold of willingness to pay is above $15,000/QALY. IMPLICATIONS: From the perspective of the Chinese Healthcare System, the treatment strategy with osimertinib postoperative adjuvant therapy is more cost-effective than the placebo strategy.

Pericancerous lymph node imaging with indocyanine green-guided near-infrared fluorescence in radical esophagectomy: Protocol for a single-center, prospective, randomized controlled clinical trial.

INTRODUCTION: The incidence and mortality rates of esophageal carcinoma are higher than those of most malignancies in humans. Radical esophagectomy is the preferred treatment for early-stage esophageal cancer. However, the extent of lymphadenectomy during radical esophagectomy remains controversial. Indocyanine green (ICG) is the most commonly used imaging agent for the diagnosis of tumors and metastatic lymph nodes in clinical settings. Thus, the main aim of this study was to evaluate pericancerous lymph nodes imaging in video-assisted thoracoscopic surgery radical esophagectomy using a near-infrared (NIR) ICG imaging system and to improve the detection rate of sentinel lymph nodes (SLNs) and overall survival of patients with esophageal cancer. METHODS: This was a single-center, prospective, randomized controlled clinical trial (allocation rate = 1:1). Forty treatment-naive esophageal cancer patients were recruited and divided into two groups: the ICG and control groups. The inclusion criteria were age, absence of preoperative neoadjuvant therapy, elective surgery, and signed informed consent. Data of participants at four different time points (preoperation, intraoperation, postoperative 1 week and 3 months) were collected and recorded. The main endpoint of this study was to explore the accuracy and false-negative rate of lymphadenectomy using NIR-ICG fluorescence imaging and to identify the location of esophageal cancer SLN combined with postoperative pathological reports. DISCUSSION: This trial will provide more evidence on the extent of lymph node dissection for esophageal cancer and contribute to the development of treatment guidelines for esophageal cancer. TRIAL REGISTRATION NUMBER: NCT04615806.

A propensity sore-matched study: Applying a modified chest tube drainage strategy in rapid rehabilitation following uni-portal thoracoscopic pulmonary wedge resection.

PURPOSE: This study aimed to compare the value of a modified chest tube drainage strategy to a traditional drainage strategy in single-port thoracoscopic pulmonary wedge resection. METHODS: From January 2019 to July 2021, we collected clinical data on 405 patients who underwent single-port thoracoscopic pulmonary wedge resection in the No.1 Department of Thoracic Surgery at Fujian Medical University Union Hospital, with 121 (29.9%) cases in the modified drainage strategy group and 284 (70.1%) cases in the traditional drainage strategy group. The propensity score matching method (Match Ratio = 1:1) was used to reduce differences in clinical characteristics between the two groups. RESULTS: Following 1:1 propensity score matching, 120 matched pairs (240 patients) were included in the study. There was no significant difference in general clinical characteristics between the two groups. There was no statistical difference in intraoperative factors except for operative times (71.42 ± 22.98 min vs. 86.80 ± 36.75 min, p < 0.001). In terms of postoperative factors, there were significant differences in postoperative chest tube duration (0.00 ± 0.00 h vs. 32.68 ± 18.51 h, p < 0.001), total drainage volume (143.03 ± 118.33 ml vs. 187.73 ± 140.82 ml, p = 0.008), postoperative hospital stay (2.61 ± 0.70 days vs. 3.27 ± 1.88 days, p < 0.001), number of additional pain relief (0.14 ± 0.40 vs. 0.42 ± 0.74, p < 0.001), facial pain score (2.7 ± 1.8 vs. 3.6 ± 2.7, p = 0.005) and adverse events (p = 0.046). Furthermore, there was a statistical difference between the two groups regarding CTCAE grade-1 complication, but no statistical difference in CTCAE grade-2 complication. CONCLUSIONS: A modified drainage strategy in single-port thoracoscopic pulmonary wedge resection is safe and feasible, allowing for less postoperative rehabilitation time, pain relief, reduced postoperative pleural effusion, and reduced clinical workload.

miR-21-5p is a Biomarker for Predicting Prognosis of Lung Adenocarcinoma by Regulating PIK3R1 Expression.

BACKGROUND: Lung cancer (LUCA) is one of the most prevalent human malignancies, and the leading cause of cancer-related deaths worldwide. Previous reports have shown that miR-21-5p plays a vital role in development of various tumors. Here, we explored the relationship between miR-21-5p/PIK3R1 axis and prognosis of patients with lung adenocarcinoma (LUAD). METHODS: MiRNAseq data, deposited in The Cancer Genome Atlas (TCGA) database, was downloaded and used to determine patterns of miR-21-5p expression in both LUAD and normal lung tissues. Statistical analyses and data visualization were performed using dbDEMC v3.0 platform, starBase v3.0 database and packages implemented in R software. Next, we employed TargetScan Human, miRDB and DIANA Tools databases to predict miR-21-5p target genes, then analyzed their expression patterns as well as prognostic value in LUAD. FINDINGS: Most human cancers overexpressed miR-21-5p. Specifically, miR-21-5p was significantly upregulated in LUAD tissues relative to normal lung tissues (P < 0.001), and this high expression was significantly correlated with poor patient prognosis (hazard ratio [HR]=1.45, P = 0.014). PIK3R1 was predicted as a miR-21-5p target gene, and both were negatively correlated (r=-0.218, P < 0.01). Notably, PIK3R1 was significantly downregulated in LUAD, relative to normal lung tissues (P < 0.01), with its overexpression significantly associated with poor prognosis of LUAD patients (HR = 0.62, P = 0.0014). CONCLUSION: miR-21-5p is a potential prognostic biomarker for LUAD patients. Moreover, it might be playing a role in LUAD progression by regulating PIK3R1 expression.

Intersegmental plane simulation based on the bronchus-vein-artery triad in pulmonary segmentectomy.

BACKGROUND: Few reliable methods to simulate and evaluate the intersegmental plane have been reported. We introduce intersegmental plane simulation based on the bronchus-vein-artery triad in three-dimensionally reconstructed images from patients who underwent segmentectomy for early lung cancer. METHODS: We collected clinical data of consecutive patients with early-stage lung cancer who underwent three-dimensional imaging-guided single-port thoracoscopic segmentectomy at Department No. 1 of Thoracic Surgery at Fujian Medical University Fujian Union Hospital from January 2019 to July 2019. Patients were divided into two groups according to the application of intersegmental plane simulation and nodule analysis: the intersegmental plane group and the non-intersegmental plane group. General clinical characteristics, operation status, and postoperative recovery were compared between groups. The three-dimensional reconstruction results in the intersegmental plane group were analyzed and summarized. RESULTS: A total of 120 patients were included (61 in the intersegmental plane group and 59 in the non-intersegmental plane group). There were no significant differences between the two groups in general characteristics (all P>0.05). All target lesions were resected in both groups. There were no significant differences between groups in operation characteristics or postoperative recovery, with the exception of the duration of chest drainage and the rate of gross margin insufficiency. There were five cases of gross margin insufficiency in the non-intersegmental plane group. With three-dimensional imaging reconstruction, a total of 131 intersegmental veins could be used to evaluate the simulated intersegmental plane in 61 patients, with an average of 2.1±0.5 veins per patient. Two patients (3.3%) had one vein that could be used to evaluate the intersegmental plane, 50 patients (82.3%) had two, seven patients (11.3%) had three, and two patients (3.3%) had four. The total number of intersegmental veins located on the simulated intersegmental plane was 124 (94.7%), with an average of 2.0±0.6 veins per patient. The accuracy of intersegmental plane simulation was 91.8% (56/61). CONCLUSIONS: The bronchus-vein-artery triad in intersegmental plane simulation can assist surgeons in preoperative planning and can facilitate complete resection of early lung cancer with sufficient surgical margins.

Centrifugal study of zone of influence during air-sparging.

Air sparging (AS) is one of the groundwater remediation techniques for remediating volatile organic compounds (VOCs) in saturated soil. However, in spite of the success of air sparging as a remediation technique for the cleanup of contaminated soils, to date, the fundamental mechanisms or the physics of air flow through porous media is not well understood. In this study, centrifugal modeling tests were performed to investigate air flow rates and the evolution of the zone of influence during the air sparging under various g-levels. The test results show that with the increase in sparging pressure the mass flow rate of the air sparging volume increases. The air mass flow rate increases linearly with the effective sparging pressure ratio, which is the difference between sparging pressure and hydrostatic pressure normalized with respect to the effective overburden pressure at the sparging point. Also the slope of mass flow rate with effective sparging pressure ratio increases with higher g-levels. This variation of the slope of mass flow rate of air sparging volume versus effective sparging pressure ratio, M, is linear with g-level confirming that the air flow through soil for a given effective sparging pressure ratio only depends on the g-level. The test results also show that with increasing sparging pressure, the zone of influence (ZOI), which consists of the width at the tip of the cone or lateral intrusion and the cone angle, will lead to an increase in both lateral intrusion and the cone angle. With a further increase in air injection pressure, the cone angle reaches a constant value while the lateral intrusion becomes the main contributor to the enlargement of the ZOI. However, beyond a certain value of effective sparging pressure ratio, there is no further enlargement of the ZOI.