Long non-coding RNA KB-1460A1.5 promotes ferroptosis by inhibiting mTOR/SREBP-1/SCD1-mediated polyunsaturated fatty acid desaturation in glioma.

Ferroptosis is a new form of regulated cell death caused by the iron-dependent peroxidation of phospholipids and is related to cell metabolism, redox homeostasis and various signalling pathways related to cancer. The long non-coding RNA (lncRNA) KB-1460A1.5 acts as a tumour suppressor gene to regulate tumour growth in gliomas, but its molecular network regulatory mechanism is still unclear. In this study, we found that KB-1460A1.5 can induce ferroptosis in glioma and enhance sensitivity to RSL3, a ferroptosis inducer. Tandem mass tag proteomics and nontargeted metabolomics suggest that KB-1460A1.5 affects polyunsaturated fatty acid metabolic processes. Gas chromatography-mass spectrometry-based medium- and long-chain fatty acid-targeted metabolomics confirmed that upregulation of KB-1460A1.5 decreased the levels of monounsaturated fatty acids, oleic acid (OA) and palmitoleic acid (PO) in glioma cells. The addition of OA and PO restored KB-1460A1.5-induced cellular ferroptosis. Molecularly, KB-1460A1.5 inhibited the mammalian target of rapamycin signalling pathway to suppress the expression of downstream sterol regulatory element-binding protein 1 (SREBP-1), thereby attenuating the stearoyl-CoA desaturase-1 (SCD1)-mediated desaturation of polyunsaturated fatty acids. Finally, an animal model of subcutaneous glioma confirmed that KB-1460A1.5 could inhibit tumour progression, SREBP-1/SCD1 expression and ferroptosis. In conclusion, increasing the expression level of KB-1460A1.5 in glioma can promote the induction of oxidative stress and ferroptosis in cancer cells through SREBP-1/SCD1-mediated adipogenesis, demonstrating therapeutic potential in preclinical models.

Squalene epoxidase promotes the chemoresistance of colorectal cancer via (S)-2,3-epoxysqualene-activated NF-κB.

BACKGROUND: While de novo cholesterol biosynthesis plays a crucial role in chemotherapy resistance of colorectal cancer (CRC), the underlying molecular mechanism remains poorly understood. METHODS: We conducted cell proliferation assays on CRC cells with or without depletion of squalene epoxidase (SQLE), with or without 5-fluorouracil (5-FU) treatment. Additionally, a xenograft mouse model was utilized to explore the impact of SQLE on the chemosensitivity of CRC to 5-FU. RNA-sequencing analysis and immunoblotting analysis were performed to clarify the mechanism. We further explore the effect of SQLE depletion on the ubiquitin of NF-κB inhibitor alpha (IκBα) and (S)-2,3-epoxysqualene on the binding of IκBα to beta-transducin repeat containing E3 ubiquitin protein ligase (BTRC) by using immunoprecipitation assay. In addition, a cohort of 272 CRC patients were selected for our clinical analyses. RESULTS: Mechanistically, (S)-2,3-epoxysqualene promotes IκBα degradation and subsequent NF-κB activation by enhancing the interaction between BTRC and IκBα. Activated NF-κB upregulates the expression of baculoviral IAP repeat containing 3 (BIRC3), sustains tumor cell survival after 5-FU treatment and promotes 5-FU resistance of CRC in vivo. Notably, the treatment of terbinafine, an inhibitor of SQLE commonly used as antifungal drug in clinic, enhances the sensitivity of CRC to 5-FU in vivo. Additionally, the expression of SQLE is associated with the prognosis of human CRC patients with 5-FU-based chemotherapy. CONCLUSIONS: Thus, our finding not only demonstrates a new role of SQLE in chemoresistance of CRC, but also reveals a novel mechanism of (S)-2,3-epoxysqualene-dependent NF-κB activation, implicating the combined potential of terbinafine for 5-FU-based CRC treatment.

Prostate cancer-associated transcript 6 (PCAT6) promotes epithelial-mesenchymal transition and stemness and worsens prognosis in patients with colorectal cancer.

Approximately 20% of colorectal cancer (CRC) patients are first diagnosed with metastatic colorectal cancer (mCRC) because they develop symptoms at an advanced stage. Despite advancements in treatment, patients with metastatic disease still experience inferior survival rates. Our objective is to investigate the association between long noncoding RNAs (lncRNAs) and prognosis and to explore their role in mCRC. In this study, we find that elevated expression of PCAT6 is independently linked to unfavourable survival outcomes in The Cancer Genome Atlas (TCGA) data, and this finding is further confirmed in CRC samples obtained from Fudan University Shanghai Cancer Center. Cell lines and xenograft mouse models are used to examine the impact of PCAT6 on tumor metastasis. Knockdown of PCAT6 is observed to impede the metastatic phenotype of CRC, as evidenced by functional assays, demonstrating the suppression of epithelial-mesenchymal transition (EMT) and stemness. Our findings show the significance of PCAT6 in mCRC and its potential use as a prognostic biomarker.

Admission Left-Arm Systolic Blood Pressure and In-Hospital Mortality After Acute Type A Aortic Dissection Repair.

AIM: Admission systolic blood pressure is a significant predictor of in-hospital mortality in patients with acute type A aortic dissection (ATAAD). While previous studies have focussed on recording the highest blood pressure value from both arms, this study aimed to evaluate the associations between blood pressure in bilateral arms and in-hospital mortality. METHODS: Data were analysed from 262 patients with ATAAD treated at a single centre. The relationship between bilateral arm blood pressure upon admission and in-hospital mortality was assessed in a logistic regression model. To comprehensively evaluate potential non-linear relationships, the association between admission bilateral systolic blood pressure (SBP) and the risk of in-hospital mortality was analysed using restricted cubic splines on a continuous scale. RESULTS: Mean age was 53.6±12.5 years and 194 (74.0%) were male. Baseline and operative data showed that ages, body mass index, smoking, left-arm SBP, left-arm diastolic blood pressure (DBP), right-arm SBP, right-arm DBP, syncope, cerebral/cardiac ischaemia, retrograde brain perfusion, Bentall procedure, coronary artery bypass grafting, and aortic valve replacement significantly differed among the left-arm SBP tertiles. In-hospital mortality was 17.6% (46 of 262). Restricted cubic splines demonstrated that the relationship between presenting left-arm SBP and in-hospital mortality followed a U-shaped curve, whereas non-linearity was not detected in the right arm. CONCLUSION: This study found a U-shaped association between admission left-arm SBP and in-hospital mortality in ATAAD surgery patients, whereas a non-linearity relationship was not detected for right-arm SBP. Low left-arm SBP independently correlated with increased in-hospital mortality, underscoring the significance of bilateral blood pressure differences in ATAAD prognosis.

Use of lymph node ratio to guide clinical decision-making concerning adjuvant radiotherapy in pT1-2N1 rectal cancer.

PURPOSE: Lymph node metastases are uncommon in pT1-2 rectal cancer. pT1-2N1 are often characterized with low tumor burden and intermediate prognosis. Therefore, adjuvant radiotherapy (ART) is controversial in these patients. This study aimed to investigate the value of ART in pT1-2 rectal cancer and evaluate the guiding role of lymph node ratio (LNR) for utilization of ART. METHODS: pT1-2N1 rectal cancer patients who received surgery without neoadjuvant radiotherapy between 2000 and 2018 with at least 12 lymph node harvest were extracted from the Surveillance, Epidemiology and End Results (SEER) database. We used time-dependent receiver operating characteristic (ROC) analysis to determine the optimal cutoff of LNR. Kaplan-Meier methods and Cox proportional hazards regression models were performed to determine the prognostic value of ART in pT1-2N1 rectal cancer patients and subgroups stratified by LNR. RESULTS: A total of 674 and 1321 patients with pT1N1 and pT2N1 rectal cancer were eligible for analysis. There was no statistical cancer-specific survival (CSS) difference in pT1N1 rectal cancer patients between receiving and not receiving ART (P = 0.464). The 5-year CSS was 89.6% and 83.2% in pT2N1 rectal cancer patients between receiving and not receiving ART, respectively (P = 0.003). A total of 7.0% was identified as the optimal cutoff value of LNR. Survival improvement offered by ART was only found in LNR ≥ 7.0% subgroup (5-year CSS: 89.5% versus 79.6%, P = 0.003) instead of LNR < 7.0% subgroup (5-year CSS: 89.9% versus 86.3%, P = 0.208). CONCLUSION: ART show substantial survival benefit in pT2N1 rectal cancer patients with LNR ≥ 7.0%, warranting the conventional adoption of ART in this subgroup.

Multi-phase optimisation model predicts manual lifting motions with less reliance on experiment-based posture data.

Optimisation-based predictive models are widely-used to explore the lifting strategies. Existing models incorporated empirical subject-specific posture constraints to improve the prediction accuracy. However, over-reliance on these constraints limits the application of predictive models. This paper proposed a multi-phase optimisation method (MPOM) for two-dimensional sagittally symmetric semi-squat lifting prediction, which decomposes the complete lifting task into three phases-the initial posture, the final posture, and the dynamic lifting phase. The first two phases are predicted with force- and stability-related strategies, and the last phase is predicted with a smoothing-related objective. Box-lifting motions of different box initial heights were collected for validation. The results show that MPOM has better or similar accuracy than the traditional single-phase optimisation (SPOM) of minimum muscular utilisation ratio, and MPOM reduces the reliance on experimental data. MPOM offers the opportunity to improve accuracy at the expense of efforts to determine appropriate weightings in the posture prediction phases. Practitioner summary: Lifting optimisation models are useful to predict and explore the human motion strategies. Existing models rely on empirical subject-specific posture constraints, which limit their applications. A multi-phase model for lifting motion prediction was constructed. This model could accurately predict 2D lifting motions with less reliance on these constraints.

Bulk and single-cell transcriptome profiling reveal necroptosis-based molecular classification, tumor microenvironment infiltration characterization, and prognosis prediction in colorectal cancer.

BACKGROUND: Necroptosis is a new form of programmed cell death that is associated with cancer initiation, progression, immunity, and chemoresistance. However, the roles of necroptosis-related genes (NRGs) in colorectal cancer (CRC) have not been explored comprehensively. METHODS: In this study, we obtained NRGs and performed consensus molecular subtyping by "ConsensusClusterPlus" to determine necroptosis-related subtypes in CRC bulk transcriptomic data. The ssGSEA and CIBERSORT algorithms were used to evaluate the relative infiltration levels of different cell types in the tumor microenvironment (TME). Single-cell transcriptomic analysis was performed to confirm classification related to NRGs. NRG_score was developed to predict patients' survival outcomes with low-throughput validation in a patients' cohort from Fudan University Shanghai Cancer Center. RESULTS: We identified three distinct necroptosis-related classifications (NRCs) with discrepant clinical outcomes and biological functions. Characterization of TME revealed that there were two stable necroptosis-related phenotypes in CRC: a phenotype characterized by few TME cells infiltration but with EMT/TGF-pathways activation, and another phenotype recognized as immune-excluded. NRG_score for predicting survival outcomes was established and its predictive capability was verified. In addition, we found NRCs and NRG_score could be used for patient or drug selection when considering immunotherapy and chemotherapy. CONCLUSIONS: Based on comprehensive analysis, we revealed the potential roles of NRGs in the TME, and their correlations with clinicopathological parameters and patients' prognosis in CRC. These findings could enhance our understanding of the biological functions of necroptosis, which thus may aid in prognosis prediction, drug selection, and therapeutics development.

HER2 status is positively associated with vessel invasion of colorectal cancer: a retrospective large cohort study.

PURPOSE: HER2-positive colorectal cancer was drawn increasing attention in recent years. Accumulating evidence showed HER2-positive metastatic colorectal cancer could benefit from HER2-targeted therapy. While HER2 expression and the relationship between HER2 status and clinicopathological characteristics of overall colorectal cancer remains largely unknown. The aim of this study was to evaluate HER2 expression in colorectal cancer and compare the clinicopathological features between HER2-positive and HER2-negative colorectal cancer. METHODS: We retrospectively analyzed 3910 primary colorectal cancer patients treated in our institution from January 2016 to December 2019. Medical records and pathology reports after surgery were collected to provide information about HER2 status and other clinicopathological characteristics. RESULTS: We identified 3347 HER2-negative and 79 HER2-positive colorectal cancer patients in our cohort. The chi-square test showed that vessel invasion was significantly more common in HER2-positive colorectal cancer patients. Crude analysis showed HER2 positive was associated with vessel invasion in colorectal cancer [OR and 95% CI 0.534 (0.341, 0.835), p = 0.006]. After adjusting for N stage, a significant association was still observed between HER2 status and vessel invasion in colorectal cancer [OR and 95% CI 0.550 (0.322, 0.941), p = 0.029]. Survival analysis showed that there was no significant difference in 3-year overall survival rate between HER2 positive and HER2 negative group (p = 0.603). CONCLUSION: Our findings indicate that the rate of HER2 positivity in colorectal cancer was relatively low, and HER2 status was strongly associated with vessel invasion while having no significant influence on the 3-year overall survival rate in colorectal cancer patients.

Different Phases in Manual Materials Handling Have Different Performance Criteria: Evidence From Multi-Objective Optimization.

A manual material handling task involves the phases of reaching, lifting, unloading, and standing up (RLUS). Understanding the mechanisms of manual material handling is important for occupational health and the development of assist devices. Predictive models are becoming popular in exploring which performance criterion is appropriate in the lifting phase. However, limited attempts have been performed on the other phases. The associated performance criterion for predicting other phases is unknown. In this study, an optimization model for predicting RLUS has been developed with the multi-objective optimization method. Two performance criteria (minimum dynamic effort and maximum balance) were studied to explore their importance in each phase. The result shows that maximum balance leads to joint angle errors 27.6% and 40.9% smaller than minimum dynamic effort in reaching and unloading phases, but 40.4% and 65.9% larger in lifting and standing up phases. When the two performance criteria are combined, the maximum balance could help improve the predicting accuracy in the reaching, lifting, and unloading phases. These findings suggest that people prefer different performance criteria in different phases. This study helps understand the differences in motion strategies in manual materials handling (MMH), which would be used to develop a more accurate predictive model.

Novel functional variants in the Notch pathway and survival of Chinese colorectal cancer.

Notch signaling pathway plays crucial roles in progression of colorectal cancer (CRC), likely affecting overall survival (OS). In a two-stage survival analysis of 1116 CRC patients in East China, we found that one locus at MINAR1 out of 133 genes in the Notch signaling pathway was significantly associated with OS (P < 1 × 10-6 , false discovery rate < 0.01). This locus containing seven single-nucleotide polymorphisms (SNPs) in high linkage disequilibrium (R2 = 1) is located on chromosome 15, of which the MINAR1 rs72430409 G allele was associated with a greater death risk (HR = 1.98, 95% CI = 1.55-2.54, P = 6.8 × 10-8 ). Further analysis of ChIP-sequencing data from the encyclopedia of DNA Elements showed that rs72430409 and rs72630408 were potential cis-regulatory elements for the MINAR1 promoter. Additional expression quantitative trait loci analysis revealed that rs72430409 G>A and rs72630408 A>G were correlated with increased MINAR1 expression levels in both blood cells and colon tissues. Dual luciferase assays revealed that the rs72430409 A allele increased MINAR1 promoter activity. The Cancer Genome Atlas data showed that expression levels of MINAR1 in CRC samples were significantly higher than that in normal colorectal tissue and that high expression of MINAR1 was associated with a shortened OS, likely via activating the epithelial mesenchymal transition (EMT) pathway as shown in the gene-set enrichment analysis. In vitro, RNAi-mediated silencing of MINAR1 led to decreased migration and proliferation in CRC cancer cells, and MINAR1 silencing could downregulate the expression of key effector genes in EMT and glycolysis. Larger cohort studies and further experiments are needed to validate our findings.

S-Nitrosylation of Plastin-3 Exacerbates Thoracic Aortic Dissection Formation via Endothelial Barrier Dysfunction.

OBJECTIVE: Thoracic aortic dissection (TAD) is a fatal disease that leads to aortic rupture and sudden death. However, little is known about the effect and molecular mechanism of S-nitrosylation (SNO) modifications in TAD formation. Approach and Results: SNO levels were higher in aortic tissues from TAD patients than in those from healthy controls, and PLS3 (plastin-3) SNO was identified by liquid chromatography-tandem mass spectrometry analysis. Furthermore, tail vein administration of endothelial-specific adeno-associated viruses of mutant PLS3-C566A (denitrosylated form) suppressed the development of TAD in mice, but the wild-type PLS3 (S-nitrosylated form) virus did not. Mechanistically, Ang II (angiotensin II)-induced PLS3 SNO enhanced the association of PLS3 with both plectin and cofilin via an iNOS (inducible nitric oxide synthase)-dependent pathway in endothelial cells. The formation of PLS3/plectin/cofilin complex promoted cell migration and tube formation but weakened adherens junction formation in Ang II-treated endothelial cells. Interestingly, denitrosylated form of PLS3 partially mitigated Ang II-induced PLS3/plectin/cofilin complex formation and cell junction disruption. Additionally, the inhibition of iNOS attenuated PLS3 SNO and the association of PLS3 with plectin and cofilin, thereby modulating endothelial barrier function. CONCLUSIONS: Our data indicate that protein SNO modification in endothelial cells modulates the progression of aortic aneurysm and dissection. The iNOS-mediated SNO of PLS3 at the Cys566 site promoted its interaction with cofilin and plectin, thus contributing to endothelial barrier disruption and pathological angiogenesis in TAD.

The Heartguard: A Humanitarian Pediatric Cardiac Surgery Program in Rural China.

BACKGROUND: Congenital heart disease (CHD) accounts for the most common birth defects in China, pressuring both the physical and mental health in children. The inaccessibility of CHD children in rural China due to financial difficulties is demanding inputs from both the government and society. The Heartguard project is a program developed to improve the delivery of CHD care in rural China. METHODS: The Heartguard project partners with county hospitals and performs CHD screening to diagnose patients with CHD in rural China. Diagnosed children with CHD who are unable to afford therapy will subsequently receive treatment sponsored by the financial partners. All patients are followed up by the local partner and visiting surgical team members. RESULTS: More than 10,000 children across 9 provinces underwent CHD screening. A total of 240 (accounting for an incidence of 2.4%) was treated by the program, of which 226 patients were managed invasively, the other 14 patients conservatively. Open surgery was performed in 162 patients, while endovascular procedures were applied in another 64. No mortality or significant complications occurred during the transfer. There was no perioperative or late death. CONCLUSION: This humanitarian cardiac surgery program is able to promote accessibility of care for CHD children in rural China. The quality of life of these patients can be improved with continuous input from the society.

Development and validation of a novel epigenetic signature for predicting prognosis in colon cancer.

Epigenetic factors play a critical role in carcinogenesis by imparting a distinct feature to the chromatin architecture. The present study aimed to develop a novel epigenetic signature for evaluating the relapse-free survival of colon cancer patients. Public microarray datasets were acquired from the Gene Expression Omnibus databases: GSE39582, GSE17538, GSE33113, and GSE37892 set. Patients from GSE39582 set were randomized 1:1 into training and internal validation series. Patients were divided into high-risk and low-risk groups in training series based on a set of 11 epigenetic factors (p < .001). The good reproducibility for the prognostic value of the epigenetic signature was confirmed in the internal validation series (p < .001), external validation series (a combination of GSE17538 set, GSE33113 set, and GSE37892 set; p = .018), and entire series (p < .001). Furthermore, a nomogram, which integrated the epigenetic signature, pathological stage, and postoperative chemotherapy, was developed based on the GSE39582 set. The time-dependent receiver operating characteristic curve at 1 year demonstrated that the comprehensive signature presented superior prognostic value than the pathological stage. In conclusion, an epigenetic signature, which could be utilized to divide colon cancer patients into two groups with significantly different risk of relapse, was established. This biomarker would aid in identifying patients who require an intensive follow-up and aggressive therapeutic intervention.

Second Primary Malignancies in Patients with Colorectal Cancer: A Population-Based Analysis.

PURPOSE: This study aimed to profile the characteristics of patients with colorectal cancer (CRC) with a second primary malignancy (SPM) and to identify patients with CRC at high risk of developing SPMs. METHODS: We retrospectively reviewed data on patients with CRC aged 20-79 years from the Surveillance, Epidemiology, and End Results (SEER) database. Eligible patients were categorized into only one primary malignancy and SPM cohorts. A competing-risk model was used to quantify associations between SPM occurrence and the multiple traits of patients. Finally, a decision curve analysis (DCA) was used to evaluate the clinical usefulness of the model by calculating net benefit. RESULTS: A total of 179,884 patients were identified, 18,285 (10.2%) of whom developed SPMs during a maximum follow-up of approximately 18 years. The median survival time after the second diagnosis was less than 4 years. The 3-year, 5-year, and 10-year cumulative risks of developing an SPM were 3.9%, 5.9%, and 10.0%, respectively. According to the multivariable competing-risk model, male colon cancer survivors, older in age, with a well-differentiated tumor and localized disease, who were treated with surgery were susceptible to SPMs. The DCA yielded a wide range of risk thresholds at which the net benefits would be obtained from our proposed model. CONCLUSION: CRC survivors remain at high risk of developing SPMs. Patients with a second diagnosis of cancer showed not only significantly worse survival but also higher cancer-specific mortality. A web-based individualized predictive tool was also provided to assist clinicians in identifying patients at high risk of developing SPMs and planning their future care management. IMPLICATIONS FOR PRACTICE: Colorectal cancer survivors remain at high risk of developing a second primary malignancy (SPM). This study aimed to profile the characteristics of patients with colorectal cancer with second primary malignancies and to further explore the risk factors related to the development of second primary malignancies, using a large population-based cohort. A clinically useful competing-risk nomogram was developed to predict the risk of SPMs based on individual clinical factors. According to the findings, older age, male sex, white or black race, localized disease, and treatment with surgery among patients with colon cancer were associated with an increased risk of developing an SPM. These findings and the proposed tool could be useful to clinicians and caregivers in the clinical counseling of patients with colorectal cancer and the development of long-term care management.

The Critical Role of Tumor Size in Predicting Prognosis for T1 Colon Cancer.

BACKGROUND: The role of horizontal growth index of tumor size in survival prediction is still underappreciated in colon cancer because of the identification of vertical infiltration index reflected by T stage. We sought to reveal the impact of T stage on the prognostic and predictive value of tumor size in colon cancer. MATERIALS AND METHODS: Data of patients with stage I-III colon cancer were extracted from Surveillance, Epidemiology, and End Results Program (SEER) and Fudan University Shanghai Cancer Center (FUSCC) databases. Harrell's concordance index (c-index) and time-dependent receiver operating characteristic curve (ROC) were used to analyze the discriminative ability of prognostic factors. RESULTS: Stratified analyses based on T stage found that the increase of T stage significantly and negatively repressed the effect of tumor size on death and recurrence risk. In addition, tumor size showed the greatest hazard ratio of cancer-specific death and relapse in T1 colon cancer. Even more importantly, the discriminatory ability of tumor size outperformed any other widely accepted prognostic clinical features in predicting cancer-specific survival (SEER: c-index 0.637, area under the ROC [AUC] 0.649; FUSCC: c-index 0.673, AUC 0.686) and disease-free survival (FUSCC: c-index 0.645, AUC 0.656) in T1 stage colon cancer. CONCLUSION: Tumor size is a critical clinical factor with considerable prognostic and predictive value for T1 colon cancer, and it should be selectively incorporated into the current staging system to facilitate prediction of death and recurrence risk. IMPLICATIONS FOR PRACTICE: To date, no consensus has been reached about the prognostic and predictive value of tumor size in colon cancer. Although tumor size is an independent prognostic factor for patients with colon cancer, the impact of tumor size on death or recurrence risk decreased notably with the increase of T stage. More importantly, the discriminative ability of tumor size outperformed any other clinical factors including N stage in patients with T1 colon cancer. Therefore, tumor size should be recommended to be incorporated into current staging systems to facilitate prognosis prediction for patients with T1 colon cancer.

FOXE1 represses cell proliferation and Warburg effect by inhibiting HK2 in colorectal cancer.

BACKGROUND: Low expression of FOXE1, a member of Forkhead box (FOX) transcription factor family that plays vital roles in cancers, contributes to poor prognosis of colorectal cancer (CRC) patients. However, the underlying mechanism remains unclear. MATERIALS AND METHODS: The effects of FOXE1 on the growth of colon cancer cells and the expression of glycolytic enzymes were investigated in vitro and in vivo. Molecular biological experiments were used to reveal the underlying mechanisms of altered aerobic glycolysis. CRC tissue specimens were used to determine the clinical association of ectopic metabolism caused by dysregulated FOXE1. RESULTS: FOXE1 is highly expressed in normal colon tissues compared with cancer tissues and low expression of FOXE1 is significantly associated with poor prognosis of CRC patients. Silencing FOXE1 in CRC cell lines dramatically enhanced cell proliferation and colony formation and promoted glucose consumption and lactate production, while enforced expression of FOXE1 manifested the opposite effects. Mechanistically, FOXE1 bound directly to the promoter region of HK2 and negatively regulated its transcription. Furthermore, the expression of FOXE1 in CRC tissues was negatively correlated with that of HK2. CONCLUSION: FOXE1 functions as a critical tumor suppressor in regulating tumor growth and glycolysis via suppressing HK2 in CRC.

Nomogram to predict the risk and survival of synchronous bone metastasis in colorectal cancer: a population-based real-world analysis.

PURPOSE: Bone metastasis (BM) can obviously affect the quality of life of patients in colorectal cancer (CRC), and the whole management of patients with BM would be attractive in current clinical practice. METHODS: A total of 52,859 patients during 2010-2015 were collected from Surveillance, Epidemiology, and End Results (SEER) database. After propensity score matching (PSM), cancer-specific survival (CCS) and overall survival (OS) with BM were adopted to assess survival probability difference. Logistic regression was used to identify risk factors for BM; COX proportion hazard regression was applied to explore prognosticators for OS in patients with BM. Subsequently, nomograms were constructed and receiver operating curves (ROCs) were used to confirm the validation of nomogram. RESULTS: Three hundred and forty-two (0.65%) patients were diagnosed with synchronous BM. After PSM, 16 variables were balanced. Tumor site, histology, grade, T stage, N stage, CEA, radiochemotherapy, surgery, and liver/lung/brain metastases were associated with BM, and histology, grade, T stage, N stage, CEA, chemotherapy, surgery, and liver/lung metastases were prognosticators for BM survival. Nomograms were applied and the ROC curve proved the predictive effects. CONCLUSION: CRC patients with BM have worse real-world survival. Nomogram can predict incidence of BM in CRC patients and survival among patients with BM.

Prognostic accuracy of different lymph node staging system in predicting overall survival in stage IV colon cancer.

PURPOSE: With emphasis of surgical management, the lymph node (LN) status has been advocated to predict prognosis in colon cancer with distant metastatic. Therefore, we tend to compare the prognostic performance of American Joint Committee on Cancer (AJCC) N-staging relative to lymph node ratio (LNR), log odds of metastatic lymph nodes (LODDS), and N-score in stage IV colon cancer. METHODS: About 20,961 patients who underwent primary surgical resection for stage IV colon cancer were extracted from Surveillance, Epidemiology, and End Results (SEER) Program database. Harrell's C statistic (C-index) and Akaike's Information Criterion (AIC) were used to distinguish the prognostic performance of the different LN-staging schemes. RESULTS: Of the 20,961 patients, 17,043 (81.3%) had been with lymph node metastasis, and the median number of examined lymph nodes (ELNs) was 15. When assessed as continuous values, the LODDS shown as the best system with greatest discriminatory power (C-index, 0.6241; AIC, 29114.29) generally and each subgroups divided by ELNs. When modeled as categorical cutoff variables for further clinical usage, the 8th AJCC N-stage outperformed the other three schemes with either ELNs less than 12 (C-index, 0.5770; AIC, 8992.638), between 12 and 25 (C-index, 0.6084; AIC, 13905.72), or more than 25(C-index, 0.6192; AIC, 3138.018) with increasing C-index and less AIC value. CONCLUSIONS: When assessed as categorical variables, N-stage performed superiorly regardless of ELNs. When assessed as a continuous variable, LODDS exhibited good discriminative ability and goodness of fit in predicting survival for colon cancer patients regardless of ELNs.

Increasing age-related survival gap among patients with colorectal cancer: a population-based retrospective study.

BACKGROUND: Survival for patients with colorectal cancer (CRC) has improved over the past decades. However, it is unclear whether older patients have benefited to the same extent as younger patients. METHODS: The Surveillance, Epidemiology, and End Results (SEER) 9 registries database was queried for CRC patients from 1975 to 2009. We presented yearly data for survival with overlying loess-smoothing lines across all age groups. Another cohort was created using the SEER 18 registries database for patients diagnosed with CRC from 1973 to 2014. Yearly data for surgery-performed rate, stage proportion, and multivariate hazard ratio were performed with overlying smoothing lines across all age groups. RESULTS: In the analysis SEER 9, 5-year cause-specific survival (CSS) of patients aged ≤ 54, 55-64, and 65-74 years showed robust increase since 1975; however, the survival of patients aged 75-84 years remained low despite modest improvement, and patients aged 85 or older even showed no survival gains since 1990. In the analysis of SEER 18, there has been a steady increase in the survival of patients aged ≤ 54, 55-64, 65-74, and 75-84 years as time period advanced; however, of CRC patients aged ≥ 85 years, the survival curves of period 1990-1999 and 2000-2012 could not be distinguished from each other presented with negligibly a small gap from the curve of 1980-1989. CONCLUSIONS: The strong interaction between age and year of diagnosis implies that older patients have benefited less over time than younger patients, especially for patients aged ≥ 85 years.

How to Carry Loads Economically: Analysis Based on a Predictive Biped Model.

Carrying heavy loads costs additional energy during walking and leads to fatigue of the user. Conventionally, the load is fixed on the body. Some recent studies showed energy cost reduction when the relative motion of the load with respect to the body was allowed. However, the influences of the load's relative motion on the user are still not fully understood. We employed an optimization-based biped model, which can generate human-like walking motion to study the load-carrier interaction. The relative motion can be achieved by a passive mechanism (such as springs) or a powered mechanism (such as actuators), and the relative motion can occur in the vertical or fore-aft directions. The connection between the load and body is added to the biped model in four scenarios (two types × two directions). The optimization results indicate that the stiffness values affect energy cost differently and the same stiffness value in different directions may have opposite effects. Powered relative motion in either direction can potentially reduce energy cost but the vertical relative motion can achieve a higher reduction than fore-aft relative motion. Surprisingly, powered relative motion only performs marginally better than the passive conditions at similar peak interaction force levels. This work provides insights into developing more economical load-carrying methods and the model presented may be applied to the design and control of wearable load-carrying devices.