Reconsidering N component of cancer staging for T1-2N0-2M0 small-cell lung cancer: a retrospective study based on multicenter cohort.

BACKGROUND: The current nodal (pN) classification still has limitations in stratifying the prognosis of small cell lung cancer (SCLC) patients with pathological classifications T1-2N0-2M0. Thus. This study aimed to develop and validate a modified nodal classification based on a multicenter cohort. MATERIALS AND METHODS: We collected 1156 SCLC patients with pathological classifications T1-2N0-2M0 from the Surveillance, Epidemiology, and End Results database and a multicenter database in China. The X-tile software was conducted to determine the optimal cutoff points of the number of examined lymph nodes (ELNs) and lymph node ratio (LNR). The Kaplan-Meier method, the Log-rank test, and the Cox regression method were used in this study. We classified patients into three pathological N modification categories, new pN#1 (pN0-#ELNs > 3), new pN#2 (pN0-#ELNs ≤ 3 or pN1-2-#LNR ≤ 0.14), and new pN#3 (N1-2-#LNR > 0.14). The Akaike information criterion (AIC), Bayesian Information Criterion, and Concordance index (C-index) were used to compare the prognostic, predictive ability between the current pN classification and the new pN component. RESULTS: The new pN classification had a satisfactory effect on survival curves (Log-rank P < 0.001). After adjusting for other confounders, the new pN classification could be an independent prognostic indicator. Besides, the new pN component had a much more accurate predictive ability in the prognostic assessment for SCLC patients of pathological classifications T1-2N0-2M0 compared with the current pN classification in the SEER database (AIC: 4705.544 vs. 4731.775; C-index: 0.654 vs. 0.617, P < 0.001). Those results were validated in the MCDB from China. CONCLUSIONS: The multicenter cohort developed and validated a modified nodal classification for SCLC patients with pathological category T1-2N0-2M0 after surgery. Besides, we propose that an adequate lymph node dissection is essential; surgeons should perform and consider the situation of ELNs and LNR when they evaluate postoperative prognoses of SCLC patients.

Transcriptome and Metabolite Conjoint Analysis Reveals the Seed Dormancy Release Process in Callery Pear.

Seed dormancy transition is a vital developmental process for seedling propagation and agricultural production. The process is precisely regulated by diverse endogenous genetic factors and environmental cues. Callery pear (Pyrus calleryana Decne) is an important rootstock species that requires cold stratification to break seed dormancy, but the mechanisms underlying pear seed dormancy release are not yet fully understood. Here, we analyzed the transcriptome profiles at three different stages of cold stratification in callery pear seeds using RNA sequencing combined with phytohormone and sugar content measurements. Significant alterations in hormone contents and carbohydrate metabolism were observed and reflected the dormancy status of the seeds. The expressions of genes related to plant hormone metabolism and signaling transduction, including indole-3-acetic acid (IAA) biosynthesis (ASAs, TSA, NITs, YUC, and AAO) genes as well as several abscisic acid (ABA) and gibberellic acid (GA) catabolism and signaling transduction genes (CYP707As, GA2ox, and DELLAs), were consistent with endogenous hormone changes. We further found that several genes involved in cytokinin (CTK), ethylene (ETH), brassionolide (BR), and jasmonic acid (JA) metabolism and signaling transduction were differentially expressed and integrated in pear seed dormancy release. In accordance with changes in starch and soluble sugar contents, the genes associated with starch and sucrose metabolism were significantly up-regulated during seed dormancy release progression. Furthermore, the expression levels of genes involved in lipid metabolism pathways were also up-regulated. Finally, 447 transcription factor (TF) genes (including ERF, bHLH, bZIP, NAC, WRKY, and MYB genes) were observed to be differentially expressed during seed cold stratification and might relate to pear seed dormancy release. Our results suggest that the mechanism underlying pear seed dormancy release is a complex, transcriptionally regulated process involving hormones, sugars, lipids, and TFs.

[Effect of maternal exposure to Curcumae Rhizoma during pregnancy on neurodevelopment and apoptosis mechanism in offspring].

Curcumae Rhizoma is a Chinese medicinal herb that is contraindicated during pregnancy. Cold-congelation and blood-stasis are corresponding syndromes to Curcumae Rhizoma. Whether syndrome-based treatment is associated with developmental neurotoxicity of Curcumae Rhizoma remains to be unclear. To verify the theory of traditional Chinese medicine of "syndrome-based treatment during pregnancy", the present study induced the mice blood stasis model by immersing mice in ice water. Pregnant C57 BL/6 wild type(WT) mice and pregnant Nrf2 knock out(KO) mice were randomly divided into control groups and Rhizoma Curcumae exposure groups. The mice were exposed to Rhizoma Curcumae during day 5 to day 18 after pregnancy. The neurodevelopment was examined to evaluate the differences of developmental neurotoxicity between normal and blood-stasis pregnant mice exposed to Rhizoma Curcumae. caspase-3 and caspase-9 activity in brain of the offspring were measured by colorimetric assays. Bcl-2 mRNA and protein expression in brain of the offspring were examined by Real-time RT-PCR and Western blot, respectively. According to the findings, C57 BL/6 mice exposed to Rhizoma Curcumae(10.0 g·kg~(-1)) had a longer positive occurring time of the surface righting reflex test of offspring and higher caspase-3 and caspase-9 activities in brain of offspring, compared with the normal control group, but with no significant change in those of blood-stasis pregnant mice offspring. However, mice exposed to Rhizoma Curcumae(10.0 g·kg~(-1)) showed no change in Bcl-2 gene expression and p38 MAPK phosphorylation in brain of the offspring. Nrf2 gene knockout using CRISPR/Cas9 resulted in a longer positive occurring time of the surface righting reflex test of offspring and higher caspase-3 and caspase-9 activities in brain of offspring. In conclusion, developmental neurotoxicity of the blood-stasis pregnant mice exposed to Rhizoma Curcumae was weaker than that of the normal pregnant mice. Nrf2 activation involved in the phenomenon of Rhizoma Curcumae of "syndrome-based treatment during pregnancy", but the upstream signal pathway mechanism value shall be further investigated.

Is there a prognostic difference among stage I lung adenocarcinoma patients with different BRAF-mutation status?

BACKGROUND: The data of the prognostic role of V-Raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations in early-stage lung adenocarcinoma (LUAD) patients is scarce. This study aimed to investigate the proportion, clinicopathological features, and prognostic significance of patients with stage I LUAD carrying BRAF mutations. METHODS: We collected 431 patients with pathological stage I LUAD from cBioPortal for Cancer Genomics and 1604 LUAD patients tested for BRAF V600E and epidermal growth factor receptor (EGFR) mutations from Shanghai Pulmonary Hospital. Survival curves were drawn by the Kaplan-Meier method and compared by log-rank test. Cox proportional hazard models, propensity-score matching (PSM), and overlap weighting (OW) were performed in this study. The primary endpoint was recurrence-free survival (RFS). RESULTS: The proportion of BRAF mutations was estimated at 5.6% in a Caucasian cohort. BRAF V600E mutations were detected in six (1.4%) patients in Caucasian populations and 16 (1.0%) patients in Chinese populations. Two BRAF V600E-mutant patients were detected to have concurrent EGFR mutations, one for 19-del and one for L858R. For pathological stage I LUAD patients, BRAF mutations were not significantly associated with worse RFS than wild-type BRAF patients (HR = 1.111; p = 0.885). After PSM and OW, similar results were presented (HR = 1.352; p = 0.742 and HR = 1.246; p = 0.764, respectively). BRAF V600E mutation status also lacked predictive significance for RFS (HR, 1.844; p = 0.226; HR = 1.144; p = 0.831 and HR = 1.466; p = 0.450, respectively). CONCLUSIONS: In this study, we demonstrated that BRAF status may not be capable of predicting prognosis in stage I LUAD patients. There is a need for more data to validate our findings.

Prognostic assessment of lung adenocarcinoma patients with early-staging diseases: a nomogram based on coagulation-related factors.

OBJECTIVES: Early-stage lung adenocarcinoma (ADC) has a great heterogeneity in prognosis that is difficult to evaluate effectively. Thus, we developed and validated an effective nomogram prognostic model based on the clinical and laboratory characteristics of stage I-IIA ADC. METHODS: We included 1585 patients with pathologically diagnosed stage I-IIA ADC who underwent surgery at Shanghai Pulmonary Hospital. The nomogram was constructed based on the peripheral blood test and coagulation test indicators and evaluated using Calibration plots, concordance index, decision curve analysis and the X-tile software. Recurrence-free survival (RFS) and overall survival (OS) were estimated by the Kaplan-Meier method and the Cox proportional hazard regression model. The primary end point of this study was RFS. RESULTS: Thrombin time and 4 clinical indicators for RFS were integrated into nomograms. A favourable agreement between the nomogram prediction and validation was observed in the calibration curves for RFS probabilities. The concordance index of the nomogram to predict RFS was 0.736 (95% confidence interval, 0.717-0.755). Moreover, significant differences were shown between the high-risk and low-risk groups in RFS and OS (P < 0.001) after effective cut-off values of risk points were found based on the nomogram. CONCLUSIONS: We established and validated a prognostic nomogram including thrombin time to predict RFS and OS of stage I-IIA ADC patients. This nomogram provided an effective prediction ability for the prognosis of stage I-IIA ADC patients.

Prognostic evaluation of stage I lung adenocarcinoma based on systematic inflammatory response.

BACKGROUND: This study aimed to construct an effective nomogram based on the clinical and laboratory characteristics to predict the prognosis of stage I lung adenocarcinoma with EGFR alteration. METHODS: A retrospective study was performed of 913 eligible patients with EGFR alteration after surgery at Shanghai Pulmonary Hospital. The peripheral blood indicators were included in the nomogram. Calibration plots, concordance index, decision curve analysis, and X-tile software were used in this study. Recurrence-free survival (RFS) and overall survival were estimated by the Kaplan-Meier method and compared using the log-rank test. RESULTS: Neutrophil to lymphocyte ratio and platelet to lymphocyte ratio were independent risk factors for RFS. The calibration curves for RFS probabilities showed good agreement between the nomogram prediction and actual observation. Furthermore, the nomogram, including neutrophil to lymphocyte ratio and platelet to lymphocyte ratio had a higher concordance index (0.732, 95% confidence interval = 0.706 to 0.758) than that without neutrophil to lymphocyte ratio or platelet to lymphocyte ratio (0.713, 95% confidence interval = 0.686 to 0.740), and decision curve analysis plots showed that the nomogram with neutrophil to lymphocyte ratio and platelet to lymphocyte ratio had better clinical practicability. Additionally, the patients were divided into 2 groups according to cutoff values of risk points, and statistically significant differences in RFS and overall survival were observed between the high-risk and low-risk groups (P < .001). CONCLUSIONS: High pretreatment levels of neutrophil to lymphocyte ratio and platelet to lymphocyte ratio were strongly associated with a worse prognosis in stage I EGFR-altered lung adenocarcinomas. Besides, the proposed nomogram with neutrophil to lymphocyte ratio and platelet to lymphocyte ratio presented a better prediction ability for the survival of those patients.

High-risk characteristics of pathological stage I lung adenocarcinoma after resection: patients for whom adjuvant chemotherapy should be performed.

Background: The objective of the present study was to identify patients with pathologic stage I lung adenocarcinoma (LUAD) who are at high risk of recurrence and assess the efficacy of adjuvant chemotherapy (ACT) in these individuals. Methods: A retrospective study was conducted on 1504 patients with pathologic stage I LUAD who underwent surgical resection at Shanghai Pulmonary Hospital and Sun Yat-sen University Cancer Center. Cox proportional hazard regression analyses were performed to identify indicators associated with a high risk of recurrence, while the Kaplan-Meier method and Log-rank test were employed to compare recurrence-free survival (RFS) and overall survival (OS) between patients with ACT and those without it. Results: Four independent indicators, including age (≥62 years), visceral pleural invasion (VPI), predominant pattern (micropapillary/solid), and lymphovascular invasion (LVI), were identified to be significantly related with RFS. Subsequently, patients were classified into high-risk and low-risk groups by LVI, VPI, and predominant pattern. The administration of ACT significantly increased both RFS (P < 0.001) and OS (P = 0.03) in the high-risk group (n = 250). Conversely, no significant difference was observed in either RFS (P = 0.45) or OS (P = 0.063) between ACT and non-ACT patients in the low-risk group (n = 1254). Conclusions: Postoperative patients with stage I LUAD with factors such as LVI, VPI, and micropapillary/solid predominant pattern may benefit from ACT.

A Nomogram Based on Atelectasis/Obstructive Pneumonitis Could Predict the Metastasis of Lymph Nodes and Postoperative Survival of Pathological N0 Classification in Non-small Cell Lung Cancer Patients.

The eighth TNM staging system proposal classifies lung cancer with partial or complete atelectasis/obstructive pneumonia into the T2 category. We aimed to develop nomograms to predict the possibility of lymph node metastasis (LNM) and the prognosis for NSCLC based on atelectasis and obstructive pneumonitis. METHODS: NSCLC patients over 20 years old diagnosed between 2004 and 2015 were selected from the Surveillance, Epidemiology, and End Results (SEER) database. The nomograms were based on risk factors that were identified by Logistic regression. The area under the receiver operating characteristic (ROC) curve (AUC) was performed to confirm the predictive values of our nomograms. Cox proportional hazards analysis and Kaplan-Meier survival analysis were also used in this study. RESULTS: A total of 470,283 patients were enrolled. Atelectasis/obstructive pneumonitis, age, gender, race, histologic types, grade, and tumor size were defined as independent predictive factors; then, these seven factors were integrated to establish nomograms of LNM. The AUC is 0.70 (95% CI: 0.694-0.704). Moreover, the Cox proportional hazards analysis and Kaplan-Meier survival analysis showed that the scores derived from the nomograms were significantly correlated with the survival of pathological N0 classification. CONCLUSION: Nomograms based on atelectasis/obstructive pneumonitis were developed and validated to predict LNM and the postoperative prognosis of NSCLC.

AMG-510 and cisplatin combination increases antitumor effect in lung adenocarcinoma with mutation of KRAS G12C: a preclinical and translational research.

BACKGROUND: The efficacy of monotherapy of AMG-510 is limited. This study explored whether the AMG-510 and cisplatin combination increases the anti-tumor effect in lung adenocarcinoma with the mutation of Kirsten rat sarcoma viral oncogene (KRAS) G12C. METHODS: Patients' data were used to analyze the proportion of KRAS G12C mutation. Besides, the next-generation sequencing data was used to uncover information about co-mutations. The cell viability assay, the concentration inhibiting 50% of cell viability (IC50) determination, colony formation, and cell-derived xenografts were conducted to explore the anti-tumor effect of AMG-510, Cisplatin, and their combination in vivo. The bioinformatic analysis was conducted to reveal the potential mechanism of drug combination with improved anticancer effect. RESULTS: The proportion of KRAS mutation was 2.2% (11/495). In this cohort with KRAS mutation, the proportion of G12D was higher than others. Besides, KRAS G12A mutated tumors had the likelihood of concurrent serine/threonine kinase 11 (STK11) and kelch-like ECH-associated protein 1 (KEAP1) mutations. KRAS G12C and tumor protein p53 (TP53) mutations could appear at the same time. In addition, KRAS G12D mutations and C-Ros oncogene 1 (ROS1) rearrangement were likely to be present in one tumor simultaneously. When the two drugs were combined, the respective IC50 values were lower than when used alone. In addition, there was a minimum number of clones among all wells in the drug combination. In in vivo experiments, the tumor size reduction in the drug combination group was more than twice that of the single drug group (p < 0.05). The differential expression genes were enriched in the pathways of phosphatidylinositol 3 kinase-protein kinase B (PI3K-Akt) signaling and extracellular matrix (ECM) proteoglycans compared the combination group to the control group. CONCLUSIONS: The anticancer effect of the drug combination was confirmed to be better than monotherapy in vitro and in vivo. The results of this study may provide some information for the plan of neoadjuvant therapy and the design of clinical trials for lung adenocarcinoma patients with KRAS G12C mutation.

A Novel Systematic Oxidative Stress Score Predicts the Survival of Patients with Early-Stage Lung Adenocarcinoma.

This study aimed to construct an effective nomogram based on the clinical and oxidative stress-related characteristics to predict the prognosis of stage I lung adenocarcinoma (LUAD). A retrospective study was performed on 955 eligible patients with stage I LUAD after surgery at our hospital. The relationship between systematic-oxidative-stress biomarkers and the prognosis was analyzed. The systematic oxidative stress score (SOS) was established based on three biochemical indicators, including serum creatinine (CRE), lactate dehydrogenase (LDH), and uric acid (UA). SOS was an independent prognostic factor for stage I LUADs, and the nomogram based on SOS and clinical characteristics could accurately predict the prognosis of these patients. The nomogram had a high concordance index (C-index) (0.684, 95% CI, 0.656-0.712), and the calibration curves for recurrence-free survival (RFS) probabilities showed a strong agreement between the nomogram prediction and actual observation. Additionally, the patients were divided into two groups according to the cut-off value of risk points based on the nomogram, and a significant difference in RFS was observed between the high-risk and low-risk groups (p < 0.0001). SOS is an independent prognostic indicator for stage I LUAD. These things considered, the constructed nomogram based on SOS could accurately predict the survival of those patients.

The clinical-histologic and prognostic characteristics in patients with a second primary non-small-cell lung cancer after a lobectomy.

OBJECTIVES: The goal of this study was to investigate whether an operation can offer survival benefits for patients with a second primary non-small-cell lung cancer (NSCLC) after a lobectomy for a first primary NSCLC and to analyse the characteristics affecting the survival of those patients. METHODS: We performed survival analyses of patients with a second primary NSCLC based on the Surveillance, Epidemiology and End Results program and used propensity score matching to reduce the potential bias and analyse the data. In addition, the primary observational end point was overall survival (OS), and the secondary observational end point was histologic migration. RESULTS: The data from 944 patients were used to perform the main analysis. A total of 36.2% of patients experienced a shift in tumour histologic type between 2 diagnoses of primary NSCLC, and this shift significantly affected OS (P = 0.0065). The median survival time in patients with surgical resection and those without an operation was 52.0 months versus 33.0 months, respectively. Patients with surgical resection at the secondary diagnosis had better survival than those without surgery (5-year OS rate: 48.0% vs 34.0%, P < 0.001). In addition, compared with a pneumonectomy and a sublobar resection, a lobectomy was the optimal surgical procedure for patients diagnosed with a second primary NSCLC after adjusting for other confounders (adjusted hazard ratio: 0.68, P < 0.01). However, in the subgroup analysis, lobar and sublobar resections could provide similar survival benefits for patients with tumour size ≤20 mm (P = 0.5). CONCLUSIONS: The operation, especially a lobectomy, can prolong OS in patients with a second primary NSCLC. Besides, sublobar resection can be performed in selected patients with tumour size ≤20 mm. Moreover, histologic migration may impact the survival of those patients with a secondary primary NSCLC.

The postoperative prognosis of skip-N2 metastasis is favorable in small-cell lung carcinoma patients with pathological N2 classification: a propensity-score-adjusted retrospective multicenter study.

Background: The study on skip-N2 metastasis in small-cell lung cancer (SCLC) is lacking. Therefore, this study aimed to explore the prognostic significance of skip-N2 metastasis based on a multicenter cohort. Methods: We collected 176 SCLC patients with pathological categories T1-4N1-2M0 from four hospitals in China. Survival curves were drawn through the Kaplan-Meier method and compared by the log-rank test. The Cox regression method was used to calculate the hazard ratio (HR) and 95% confidence interval of the characteristics for cancer-specific survival (CSS). Two propensity-score methods were used to reduce the bias, including the inverse probability of treatment weighting (IPTW) and propensity-score matching (PSM). Results: This multicenter database included 64 pN1 patients, 63 non-skip-N2 cases, and 49 skip-N2 cases. Skip-N2 and the non-skip-N2 patients had gap CSS rates (skip-N2 no versus yes: 41.0% versus 62.0% for 1-year CSS, 32.0% versus 46.0% for 2-year CSS, and 20.0% versus 32.0% for 3-year CSS). After PSM, there were 32 pairs of patients to compare survival differences between N2 and skip-N2 diseases, and 34 pairs of patients to compare prognostic gaps between N1 and skip-N2 diseases, respectively. The results of IPTW and PSM both suggested that skip-N2 cases had better survival outcomes than the non-skip-N2 cases (IPTW-adjusted HR = 0.578; PSM-adjusted HR = 0.510; all log-rank p < 0.05). Besides, the above two analytic methods showed no difference in prognoses between pN1 and skip-N2 diseases (all log-rank p > 0.05). Conclusions: Skip-N2 patients were confirmed to have a better prognosis than non-skip-N2 patients. Besides, there was no survival difference between pN1 and skip-N2 cases. Therefore, we propose that the next tumor-node-metastasis staging system needs to consider the situation of skip metastasis with lymph nodes in SCLC.

The Clinical and Prognostic Characteristics of Primary Salivary Gland-Type Carcinoma in the Lung: A Population-Based Study.

This study aimed to explore the clinical and prognostic characteristics of primary salivary gland-type carcinoma (SGC). The entire cohort from the Surveillance, Epidemiology, and End Results database was used to calculate the SGC proportion. In total, 253,096 eligible patients, including 165,715 adenocarcinomas (ADCs), 87,062 squamous cell carcinomas (SCCs), and 319 SGCs, were selected to perform survival analyses. The data of 42 SGC patients from our hospital showed postoperative survival. Overall survival (OS) curves for different histological and surgical types were presented. The proportion of primary SGCs was 0.8 per 1000 patients. Patients with age ≤ 64 years old had a much higher proportion of SGC than those patients with age >64 years old. After adjusting for other confounders, among ADCs, SCCs, and SGC, SGCs had the best prognosis (HR 0.361, p < 0.001). Moreover, the 5-year OS rates of SGC patients were 55% and 7% in the group with surgery or without surgery, respectively (p < 0.001). The data of 42 patients from our hospital also showed a good survival of SGCs. Lobectomy improved the survival of SGCs significantly (adjusted HR 0.439, p = 0.016). In conclusion, pulmonary SGCs had the best prognosis among ADCs, SCCs, and SGCs. In addition, lobectomy could further improve the prognostic outcomes of SGCs.

SMC1A regulated by KIAA1429 in m6A-independent manner promotes EMT progress in breast cancer.

As a component of N6-methyladenosine (m6A) "writers," KIAA1429 was reported to promote breast cancer proliferation and growth in m6A-independent manners. However, the related mechanism of KIAA1429 in breast cancer metastasis has not been reported. In the present study, we found KIAA1429 could significantly promote the migration and invasion of breast cancer cells. Then we demonstrated that knockdown of KIAA1429 could impede breast cancer metastasis in nude mice in vivo. The level of SNAIL expression and epithelial-mesenchymal transition (EMT) progress was positively related with KIAA1429. Furthermore, we confirmed that the suppression of cell migration, invasion, and EMT progress by knockdown of KIAA1429 could be reversed by the upregulation of SNAIL. However, structural maintenance of chromosomes 1A (SMC1A), not KIAA1429, bound with the SNAIL promoter region directly and promoted the transcription of SNAIL. Then we confirmed that KIAA1429 could bind to the motif in the 3' UTR of SMC1A mRNA directly and enhance SMC1A mRNA stability. In conclusion, our study revealed a novel mechanism of the KIAA1429/SMC1A/SNAIL axis in the regulation of metastasis of breast cancer. Moreover, it first provided detailed investigation of how KIAA1429 regulated the targeted gene expression at posttranscriptional levels as an RNA binding protein unrelated to its m6A modification.

A clinical risk model for assessing the survival of patients with stage IA-IIA non-small cell lung cancer after surgery.

Background: The survival of patients with stage IA-IIA non-small cell lung cancer (NSCLC) after surgery is heterogeneous. This study aimed to construct a prognostic risk model to predict the overall survival (OS) of these patients. Methods: Data from patients (n=9,914) from the Surveillance Epidemiology and End Results (SEER) database were analyzed. The cases were randomly divided into the training and the validation groups. Patients from the Shanghai Pulmonary Hospital (n=270) were also included as an external cohort. Independent significant factors affecting survival in the training cohort were used to construct a nomogram. The precision was evaluated using the concordance index (C-index) and calibration plots. The X-tile software was used to confirm the optimal cut-off value to classify the patients. Results: Sex, age at diagnosis, tumor size, visceral pleura invasion (VPI), tumor grade, and the number of examined lymph nodes were deemed independent prognostic factors and were selected to establish the nomogram. The C-indices of the nomogram for predicting OS were 0.671 [95% confidence interval (CI): 0.653-0.689] in the training group, and 0.668 (95% CI: 0.650-0.687) and 0.707 (95% CI: 0.651-0.763) in the validation and the testing groups, respectively. The cut-off value of risk points was 106.0, which stratified the patients into high-risk and low-risk groups. The high-risk patients had shorter 5-year OS than low-risk patients (P<0.001). Conclusions: The established nomogram could evaluate the survival in patients with stage IA-IIA NSCLC after surgery and may provide prognostic information for clinicians to make decisions in the management of adjuvant therapy.

A long waiting time from diagnosis to treatment decreases the survival of non-small cell lung cancer patients with stage IA1: A retrospective study.

Objective: The prognostic effect of delayed treatment on stage IA1 non-small cell lung cancer (NSCLC) patients is still unclear. This study aimed to explore the association between the waiting time before treatment and the prognosis in stage IA1 NSCLC patients. Methods: Eligible patients diagnosed with pathological stage IA1 NSCLC were included in this study. The clinical endpoints were overall survival (OS) and cancer-specific survival (CSS). The Kaplan-Meier method, the Log-rank test, univariable, and multivariable Cox regression analyses were used in this study. Propensity score matching was used to reduce the bias of data distribution. Results: There were eligible 957 patients in the study. The length of waiting time before treatment stratified the survival in patients [<3 months vs. ≥3-months, unadjusted hazard ratio (HR) = 0.481, P = 0.007; <2 months vs. ≥2-months, unadjusted HR = 0.564, P = 0.006; <1 month vs. ≥1-month, unadjusted HR = 0.537, P = 0.001]. The 5-year CSS rates were 95.0% and 77.0% in patients of waiting time within 3 months and over 3 months, respectively. After adjusting for other confounders, the waiting time was identified as an independent prognostic factor. Conclusions: A long waiting time before treatment may decrease the survival of stage IA1 NSCLC patients. We propose that the waiting time for those patients preferably is less than one month and should not exceed two months.

The characterization of tumor microenvironment infiltration and the construction of predictive index based on cuproptosis-related gene in primary lung adenocarcinoma.

Objective: We aimed to use the cancer genome atlas and gene expression omnibus databases to explore the characterization of tumor microenvironment (TME) infiltration and construct a predictive index of prognosis and treatment effect based on cuproptosis-related genes (CRGs) in primary lung adenocarcinoma (LUAD). Methods: We described the alterations of CRGs in 954 LUAD samples from genetic and transcriptional fields and evaluated their expression patterns from three independent datasets. We identified two distinct molecular subtypes and found that multi-layer CRG alterations were correlated with patient clinicopathological features, prognosis, and TME cell infiltrating characteristics. Then, a cuproptosis scoring system (CSS) for predicting the prognosis was constructed, and its predictive capability in LUAD patients was validated. Results: Two molecular subtypes of cuproptosis (Copper Genes cluster A and cluster B) in LUAD were identified. Copper Genes cluster B had better survival than those with Copper Genes cluster A (p <0.01). Besides, we found that the infiltration of activated CD4+ T cells, natural killer T cells, and neutrophils was stronger in cluster A than in cluster B. Then, we constructed a highly accurate CSS to predict the prognosis, targeted therapy effect, and immune response. Compared with the low-CSS subgroup, the mutations of the TP53, MUC16, and TTN genes were more common in the high-CSS subgroup, while the mutation of TP53, TTN, and CSMD3 genes were more common in the low-CSS subgroup than in high-CSS subgroup. The low-score CSS group had an inferior survival than high-score CSS group (p <0.01). In addition, CSS presented good ability to predict the immune response (area under curve [AUC], 0.726). Moreover, AZD5363 and AZD8186 were the inhibitors of AKT and PI3K, respectively, and had lower IC50 and AUC in the low-score CSS group than it in the high-score CSS group. Conclusions: CRGs are associated with the development, TME, and prognosis of LUAD. Besides, a scoring system based on CRGs can predict the efficacy of targeted drugs and immune response. These findings may improve our understanding of CRGs in LUAD and pave a new path for the assessment of prognosis and the development of more effective targeted therapy and immunotherapy strategies.

Effects of shear stress on differentiation of stem cells into endothelial cells.

Stem cell transplantation is an appealing potential therapy for vascular diseases and an indispensable key step in vascular tissue engineering. Substantial effort has been made to differentiate stem cells toward vascular cell phenotypes, including endothelial cells (ECs) and smooth muscle cells. The microenvironment of vascular cells not only contains biochemical factors that influence differentiation but also exerts hemodynamic forces, such as shear stress and cyclic strain. More recently, studies have shown that shear stress can influence the differentiation of stem cells toward ECs. A deep understanding of the responses and underlying mechanisms involved in this process is essential for clinical translation. This review highlights current data supporting the role of shear stress in stem cell differentiation into ECs. Potential mechanisms and signaling cascades for transducing shear stress into a biological signal are proposed. Further study of stem cell responses to shear stress will be necessary to apply stem cells for pharmacological applications and cardiovascular implants in the realm of regenerative medicine.

Newly synthesized phenanthroimidazole derivatives L082 as a safe anti-tumor and anti-injury inflammation bifunctional compound.

Chemotherapy drugs exerts beneficial antitumor activity before and after cancer surgery. Post-injury complications are a potential hazard after surgical tumor resection. Inflammation caused by surgical stress is known to promote the progression of post-injury complications. Recent studies have found that chemotherapy drugs can promote post-injury inflammatory response, leading to increased post-injury complications. Imidazole derivatives have effective anticancer activity. However, the impact of post-operative inflammation caused by imidazole derivatives is unclear. In this study, two novel phenanthroimidazole derivatives (L082 and L142) were synthesized and characterized. These compounds showed significant inhibitory effects on different tumor cells. The compound L082 also inhibited liver cancer in vivo. In addition, L082 played a significant role in inhibiting the accumulation of inflammatory cells and promoting the elimination of inflammatory cells at the incision, which may be related to inhibiting the production of ROS and NO in oxidative and nitric stress. These results suggest that L082 can be used as a bifunctional drug to suppress tumors and reduce post-injury inflammation complications.

Rapamycin enhances the sensitivity of ER­positive breast cancer cells to tamoxifen by upregulating p73 expression.

A total of 70% of breast cancers express the estrogen receptor (ER)α; therefore, targeting the ER may be an effective endocrine therapy with which to inhibit breast cancer growth. Tamoxifen is the most common­used clinically used drug for the treatment of advanced or metastatic ER­positive (ER+) breast cancer. However, a substantial proportion of patients become resistant to endocrine therapies. To overcome this limitation, in this stud, we sought to maximize the benefits associated with tamoxifen therapy via drug combination strategies. We demonstrated that rapamycin, an FDA­approved mammalian target of rapamycin (mTOR) inhibitor, enhanced the effects of endocrine therapy with tamoxifen, and the concentration of tamoxifen required for ER+ breast cancer cell growth inhibition was substantially reduced. Moreover, treatment with rapamycin plus tamoxifen significantly inhibited tumor growth in vivo. In addition, this synergistic effect may be mediated by the induction of p73. We revealed a novel mechanism in which p73 increases ERα expression by directly binding to the promoter region of the ERα gene. Taken together, the findings of this study indicate that combination therapy with rapamycin and tamoxifen underlying p73­mediated ERα expression may provide new insight into the drug combination for the treatment of ER+ breast cancer.