Development and validation of a vesicle-mediated transport-associated gene signature for predicting prognosis and immune therapy response in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a malignant tumor with a poor prognosis. The progression of numerous malignancies has been linked to abnormal vesicle-mediated transport-related gene (VMTRG) expression. The prognostic importance of VMTRGs in HCC is uncertain nonetheless. METHODS: Utilizing HCC data from TCGA and ICGC, we employed univariate cox analysis, unsupervised clustering, and lasso analysis to construct molecular subtypes and prognostic signature of HCC based on the prognostic-associated VMTRGs expression levels. Subsequently, we validated the expression levels of the signature genes. We investigated the probable pathways using gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA). Six methods were utilized to compare immune cell infiltration between two risk groups. Moreover, the "pRRophetic" algorithm was utilized to test the drug sensitivity of both groups. RESULTS: We identified two distinct subtypes with divergent biological behaviors and immune functionality through unsupervised clustering. Subtype C1 demonstrated a poorer prognosis. A prognostic signature incorporating two VMTRGs (KIF2C and RAC1) was formulated. Immunohistochemistry and qRT-PCR analyses unveiled a significant upregulation of these pivotal genes within HCC tissues. The prognosis was worse for the high-risk group, which also had a higher clinicopathological grade, higher levels of tumor mutation burden (TMB), a higher immunological infiltration of CD8 + T cells, a higher expression of immune checkpoints, and enhanced immunotherapy efficacy. These two risk groups also have varied chemotherapy drug sensitivities. CONCLUSIONS: Based on VMTRGs, we have developed a signature that assists in accurate prognosis prediction and formulating personalized treatment strategies for HCC patients.

Development and validation of a ubiquitin-proteasome system gene signature for prognostic prediction and immune microenvironment evaluation in hepatocellular carcinoma.

BACKGROUND: The ubiquitin proteasome has a major role in the development of many tumors. However, the prognostic importance of ubiquitin proteasome-system genes (UPSGs) in hepatocellular carcinoma (HCC) is not fully defined. METHODS: The TCGA and ICGC datasets were utilized to obtain transcriptional profiling data as well as clinicopathological information about HCC. The 3-UPSGs signature for the TCGA cohort was developed via univariate and LASSO Cox regression analyses. Differential expression of genes was demonstrated by qRT-PCR and immunohistochemistry (IHC). Biological pathways were studied using GSVA and GSEA. Six algorithms were used to compare immune infiltration between the two risk groups. Furthermore, drug sensitivity was measured using the "pRRophetic" R package. The predictive capacity of the 3-UPSGs signature for sensitivity to immunotherapy was also explored. Moreover, we performed a pan-cancer analysis of the 3-UPSGs signature. RESULTS: A risk model containing 3 UPSGs (DCAF13, CDC20 and PSMB5) was developed. IHC and qRT-PCR results showed that signature genes were significantly overexpressed in HCC tissues. The high-risk group had a worse prognosis, with a higher clinicopathological grade, higher levels of tumor mutation burden (TMB), elevated levels of immune checkpoint (IC) expression, as well as increased sensitivity to immunotherapy. The two risk groups also differ in their sensitivity to chemotherapeutic drugs. Furthermore, the three UPSGs may play crucial roles in the progression of multiple types of cancers. CONCLUSION: We created a 3-UPSGs signature to estimate the prognosis of HCC and to assist in individualized treatment.

Survival nomogram for high-grade bladder cancer patients after surgery based on the SEER database and external validation cohort.

Background: The aim of this study was to develop a comprehensive and effective nomogram for predicting overall survival (OS) rates in postoperative patients with high-grade bladder urothelial carcinoma. Methods: Patients diagnosed with high-grade urothelial carcinoma of the bladder after radical cystectomy (RC) between 2004 and 2015 in the Surveillance, Epidemiology, and End Results (SEER) database were enrolled. We randomly split (7:3) these patients into the primary cohort and the internal validation cohort. Two hundred eighteen patients from the First Affiliated Hospital of Nanchang University were collected as the external validation cohort. Univariate and multivariate Cox regression analyses were carried out to seek prognostic factors of postoperative patients with high-grade bladder cancer (HGBC). According to these significant prognostic factors, a simple-to-use nomogram was established for predicting OS. Their performances were evaluated using the concordance index (C-index), the receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). Results: The study included 4,541 patients. Multivariate Cox regression analysis demonstrated that T stage, positive lymph nodes (PLNs), age, chemotherapy, regional lymph nodes examined (RLNE), and tumor size were correlated with OS. The C-index of the nomogram in the training cohort, internal validation cohort, and external validation cohort were 0.700, 0.717, and 0.681, respectively. In the training, internal validation, and external validation cohorts, the ROC curves showed that the 1-, 3-, and 5-year areas under the curve (AUCs) were higher than 0.700, indicating that the nomogram had good reliability and accuracy. The results of calibration and DCA showed good concordance and clinical applicability. Conclusion: A nomogram was developed for the first time to predict personalized 1-, 3-, and 5-year OS in HGBC patients after RC. The internal and external validation confirmed the excellent discrimination and calibration ability of the nomogram. The nomogram can help clinicians design personalized treatment strategies and assist with clinical decisions.

Corrigendum: Machine learning in non-small cell lung cancer radiotherapy: a bibliometric analysis.

[This corrects the article DOI: 10.3389/fonc.2023.1082423.].

Machine learning in non-small cell lung cancer radiotherapy: A bibliometric analysis.

Background: Machine learning is now well-developed in non-small cell lung cancer (NSCLC) radiotherapy. But the research trend and hotspots are still unclear. To investigate the progress in machine learning in radiotherapy NSCLC, we performed a bibliometric analysis of associated research and discuss the current research hotspots and potential hot areas in the future. Methods: The involved researches were obtained from the Web of Science Core Collection database (WoSCC). We used R-studio software, the Bibliometrix package and VOSviewer (Version 1.6.18) software to perform bibliometric analysis. Results: We found 197 publications about machine learning in radiotherapy for NSCLC in the WoSCC, and the journal Medical Physics contributed the most articles. The University of Texas MD Anderson Cancer Center was the most frequent publishing institution, and the United States contributed most of the publications. In our bibliometric analysis, "radiomics" was the most frequent keyword, and we found that machine learning is mainly applied to analyze medical images in the radiotherapy of NSCLC. Conclusion: The research we identified about machine learning in NSCLC radiotherapy was mainly related to the radiotherapy planning of NSCLC and the prediction of treatment effects and adverse events in NSCLC patients who were under radiotherapy. Our research has added new insights into machine learning in NSCLC radiotherapy and could help researchers better identify hot research areas in the future.

The efficacy of adding hyperthermia to the treatment of advanced NSCLC patients based on the states of EGFR.

BACKGROUND: The study aims to explore the efficacy of adding hyperthermia to the treatment of advanced NSCLC patients based on the states of epidermal growth factor receptor (EGFR). PATIENTS AND METHODS: We included 205 advanced NSCLC patients who were received hyperthermia plus other treatment (hyperthermia group) or non- hyperthermia and other treatments (non- hyperthermia group). The OS and progression free survival (PFS) were retrospectively estimated. Using Kaplan-Meier and the log-rank test compare the OS and PFS between the groups. RESULTS: The median follow-up was 22 months. The Univariate analysis have shown that 1-year OS and PFSfirst rates in the hyperthermia group and non- hyperthermia group were 83.3% vs 71.5% (P=0.010) and 62.0% vs 42.7% (P=0.001). The subgroup analyses revealed that patients didn't have EGFR mutant who received hyperthermia had significantly higher 1 year OS and PFSfirst rates than those treated with non- hyperthermia (OS: 79.1% vs 65.2% P=0.037, PFS: 64.2% vs 36.5%, P=0.001). For patients with EGFR mutation, there was no significant difference between the two groups. The PFSfirst in first-line and PFSpost in posterior-line was no significant difference between the groups. CONCLUSIONS: This retrospective study revealed that adding hyperthermia to the treatment of NSCLC patients without EGFR mutation had better prognosis than those who did not adding hyperthermia to the regimen. Moreover, adding hyperthermia in first-line or in posterior-line treatment was no significant difference. However, these results need more prospective studies to confirm the conclusions.

Predictive nomograms for early death in metastatic bladder cancer.

Background: Metastatic bladder cancer (MBC) is an incurable malignancy, which is prone to early death. We aimed to establish models to evaluating the risk of early death in patients with metastatic bladder cancer. Methods: The data of 1,264 patients with MBC registered from 2010 to 2015 were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. We utilized X-tile software to determine the optimal cut-off points of age and tumor size in diagnosis. Univariate and multivariate logistic regression analyses were used to identify significant independent risk factors for total early death and cancer-specific early death, then we construct two practical nomograms. In order to validate our prediction models, we performed calibration plots, receiver operating characteristics (ROCs) curves, decision curve analysis (DCA) and clinical impact curve (CIC). Result: A total of 1,216 patients with MBC were included in this study. 463 patients died prematurely (≤3 months), and among them 424 patients died of cancer-specific early death. The nomogram of total premature death was created by surgery, chemotherapy, tumor size, histological type, liver metastases, and nomogram of cancer-specific early death was based on surgery, race, tumor size, histological type, chemotherapy, and metastases (liver, brain). Through the verify of calibration plots, receiver operating characteristics (ROCs) curves, decision curve analysis (DCA) and clinical impact curve (CIC), we concluded that nomogram were a valid tool with excellent clinical utility to help clinicians predict premature death in MBC patients. Conclusions: The nomograms derived from the analysis of patients with MBC, which can provide refined prediction of premature death and furnish clinicians with useful ideas for patient-specific treatment options and follow-up scheduling.

The molecular structure and role of LECT2 or CHM-II in arthritis, cancer, and other diseases.

Leukocyte cell-derived chemotaxin-2 (LECT2 or LECT-2), also called chondromodulin II (ChM-II or CHM2) plays a versatile role in various tissues. It was first identified as a chemotactic factor to promote the migration of neutrophils. It was also reported as a hepatokine to regulate glucose metabolism, obesity, and nonalcoholic fatty liver disease. As a secreted factor, LECT2 binds to several cell surface receptors CD209a, Tie1, and Met to regulate inflammatory reaction, fibrogenesis, vascular invasion, and tumor metastasis in various cell types. As an intracellular molecule, it is associated with LECT2-mediated amyloidosis, in which LECT2 misfolding results in insoluble fibrils in multiple tissues such as the kidney, liver, and lung. Recently, LECT2 was found to be associated with the development of rheumatoid arthritis and osteoarthritis, involving the dysregulation of osteoclasts, mesenchymal stem cells, osteoblasts, chondrocytes, and endothelial cells in the bone microenvironment. LECT2 is implicated in the development of cancers, such as hepatocellular carcinoma via MET-mediated PTP1B/Raf1/ERK signaling pathways and is proposed as a biomarker. The mechanisms by which LECT2 regulates diverse pathogenic conditions in various tissues remain to be fully elucidated. Further research to understand the role of LECT2 in a tissue tropism-dependent manner would facilitate the development of LECT2 as a biomarker for diagnosis and therapeutic target.

Current research progress in targeted anti-angiogenesis therapy for osteosarcoma.

Osteosarcoma (OS) is the most common primary malignant bone tumour with a peak in incidence during adolescence. Delayed patient presentation and diagnosis is common with approximately 15% of OS patients presenting with metastatic disease at initial diagnosis. With the introduction of neoadjuvant chemotherapy in the 1970s, disease prognosis improved from 17% to 60%-70% 5-year survival, but outcomes have not significantly improved since then. Novel and innovative therapeutic strategies are urgently needed as an adjunct to conventional treatment modalities to improve outcomes for OS patients. Angiogenesis is crucial for tumour growth, metastasis and invasion, and its prevention will ultimately inhibit tumour growth and metastasis. Dysregulation of angiogenesis in bone microenvironment involving osteoblasts and osteoclasts might contribute to OS development. This review summarizes existing knowledge regarding pre-clinical and developmental research of targeted anti-angiogenic therapy for OS with the aim of highlighting the limitations associated with this application. Targeted anti-angiogenic therapies include monoclonal antibody to VEGF (bevacizumab), tyrosine kinase inhibitors (Sorafenib, Apatinib, Pazopanib and Regorafenib) and human recombinant endostatin (Endostar). However, considering the safety and efficacy of these targeted anti-angiogenesis therapies in clinical trials cannot be guaranteed at this point, further research is needed to completely understand and characterize targeted anti-angiogenesis therapy in OS.

The role of glial cell line-derived neurotrophic factor family member artemin in neurological disorders and cancers.

Artemin (ARTN) is a member of the glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs), which encompasses family members, GDNF, neurturin (NRTN) and persephin (PSPN). ARTN is also referred to as Enovin or Neublastin, and bears structural characteristics of the TGF-ß superfamily. ARTN contains a dibasic cleavage site (RXXR) that is predicted to be cleaved by furin to yield a carboxy-terminal 113 amino acid mature form. ARTN binds preferentially to receptor GFRα3, coupled to a receptor tyrosine kinase RET, forming a signalling complex for the regulation of intracellular pathways that affect diverse outcomes of nervous system development and homoeostasis. Standard signalling cascades activated by GFLs via RET include the phosphorylation of mitogen-activated protein kinase or MAPK (p-ERK, p-p38 and p-JNK), PI3K-AKT and Src. Neural cell adhesion molecule (NCAM) is an alternative signalling receptor for ARTN in the presence of GFRα1, leading to activation of Fyn and FAK. Further, ARTN also interacts with heparan sulphate proteoglycan syndecan-3 and mediates non-RET signalling via activation of Src kinases. This review discusses the role of ARTN in spinal cord injury, neuropathic pain and other neurological disorders. Additionally, ARTN plays a role in non-neuron tissues, such as the formation of Peyer's patch-like structures in the lymphoid tissue of the gut. The emerging role of ARTN in cancers and therapeutic resistance to cancers is also explored. Further research is necessary to determine the function of ARTN in a tissue-specific manner, including its signalling mechanisms, in order to improve the therapeutic potential of ARTN in human diseases.

Molecular structure and the role of high-temperature requirement protein 1 in skeletal disorders and cancers.

Human high-temperature requirement protein 1 (HTRA1) is a member of serine proteases and consists of four well-defined domains-an IGFBP domain, a Kazal domain, a protease domain and a PDZ domain. HTRA1 is a secretory protein and also present intracellularly and associated with microtubules. HTRA1 regulates a broad range of physiological processes via its proteolytic activity. This review examines the role of HTRA1 in bone biology, osteoarthritis, intervertebral disc (IVD) degeneration and tumorigenesis. HTRA1 mediates diverse pathological processes via a variety of signalling pathways, such as TGF-ß and NF-κB. The expression of HTRA1 is increased in arthritis and IVD degeneration, suggesting that HTRA1 protein is attributed to cartilage degeneration and disease progression. Emerging evidence also suggests that HTRA1 has a role in tumorigenesis. Further understanding the mechanisms by which HTRA1 displays as an extrinsic and intrinsic regulator in a cell type-specific manner will be important for the development of HTRA1 as a therapeutic target.

Effect of alkali concentration on digestibility and absorption characteristics of rice residue protein isolates and lysinoalanine.

The effect of alkali concentration on the digestibility and absorption characteristics of rice residue protein isolates (RPI) and lysinoalanine (LAL) was studied. When NaOH concentration was 0.03 M, the in vitro digestibility of RPI reached a maximum, and when NaOH concentration was higher than 0.03 M, the in vitro digestibility decreased. Alkali treatment reduced the release of all amino acids, especially arginine, lysine, phenylalanine, tyrosine, cysteine, and threonine. LAL only released 2.65-9.28% of the total LAL content, which was mainly combined with longer peptide chains, and the molecular weight was mostly accumulated between 1000 Da and 3000 Da. The experimental model of rats in the small intestine perfusion showed that the high alkali concentration significantly reduced the absorption rate of RPI, and LAL had no specific absorption site in the small intestine of rats, and was not available for intestinal absorption.

Elevated serum total bilirubin levels are negatively associated with major diabetic complications among Chinese senile diabetic patients.

AIMS: This study aimed to evaluate the association between total bilirubin (TBiL) and major diabetic complications among Chinese senile diabetic patients. METHODS: A cross-sectional study was conducted in all the cadre sanitariums in Beijing, between May 2012 and December 2014. All the diagnoses of diabetic complications were extracted from the medical records including chronic kidney disease, retinopathy, peripheral vascular disease, coronary heart disease, and ischemic stroke. RESULTS: The mean age of the 1839 senile diabetic patients were 87.4±4.0 (80-102years) and mean TBiL level was 13.2±6.0µmol/L. The prevalence of chronic kidney disease, retinopathy, peripheral vascular disease, coronary heart disease and ischemic stroke was 13.8%, 17.8%, 5.8%, 62.5%, and 44.5%, respectively. TBiL level was negatively correlated with age, weight, SBP, TC, FBG, 2hPG, diabetic duration and positively correlated with HDL-C. Prevalence of all five diseases gradually decreased with the increase of TBiL level (p<0.05). Also, number of diabetic complications showed a decreasing trend along with TBiL tertiaries. After adjusted age, education, marital status, current smoking, current drinking, physical activity ≥0.5h/day, BMI, hypertension, dyslipidemia, treatment and control status of diabetes, patients with higher TBiL level were at significantly decreased ORs for prevalence of major diabetic complications. The ORs were 0.97 (95%CI: 0.96-0.99), 0.90 (95%CI: 0.87-0.93), 0.98 (95%CI: 0.97-0.99), 0.97 (95%CI: 0.95-.99) and 0.98 (95%CI: 0.97-0.99) for chronic kidney disease, retinopathy, peripheral vascular disease, coronary heart disease and ischemic stroke (p<0.005). Similar results were obtained when TBiL was used as tertiary variable. CONCLUSION: Higher TBiL was significantly associated with lower prevalence of major diabetic complication among senile diabetic patients, and this association was graded with TBiL level and independent of age and control status of diabetes.

Selective nickel- and manganese-catalyzed decarboxylative cross coupling of some α,ß-unsaturated carboxylic acids with cyclic ethers.

A nickel- and manganese-catalyzed decarboxylative cross coupling of α, ß-unsaturated carboxylic acids with cyclic ethers such as tetrahydrofuran and 1, 4-dioxane was developed. Oxyalkylation was achieved when nickel acetate was used as catalyst, while manganese acetate promoted the reaction of alkenylation.

Estimation of 10-year risk of fatal and nonfatal ischemic cardiovascular diseases in Chinese adults.

BACKGROUND: Stroke is much more prevalent than coronary heart disease in China; thus, any risk prediction model only for coronary heart disease may not be appropriate in application. Our objective is to develop a cardiovascular risk prediction model appropriate for the Chinese population. METHODS AND RESULTS: Cox proportional hazards regression was used to develop sex-specific optimal 10-year risk prediction models for ischemic cardiovascular disease (ICVD; including ischemic stroke and coronary events) from 17 years of follow-up data from the USA-PRC Collaborative Study of Cardiovascular Epidemiology cohort, in which 9903 participants were followed up every 2 years until 2000, and 371 ICVD events (266 strokes and 105 coronary heart disease events) occurred. The models showed ICVD was positively related to age, systolic blood pressure, serum total cholesterol, body mass index, current smoking status, and diabetes mellitus in both men and women. When the models were applied to the 17,329 participants in the China Multicenter Collaborative Study of Cardiovascular Epidemiology cohort, the areas under the receiver operating characteristic curve were 0.796+/-0.036 for men and 0.791+/-0.036 for women. The simplified point score model resulted in similar c statistics. Comparison of the observed with the estimated incidence of ICVD at different risk levels showed satisfactory precision. Meanwhile, application of recalibrated Framingham models significantly overestimated the coronary heart disease risk in both men (by approximately 97%) and women (by approximately 228%). CONCLUSIONS: The Cox regression prediction models and simplified point score model have satisfying predictive capability for estimating the 10-year integrated cardiovascular risk in Chinese, in whom stroke is the predominant cardiovascular disease.

Total cholesterol and mortality in China, Poland, Russia, and the US.

PURPOSE: To examine the relationships of total and cause-specific mortality to serum cholesterol in four diverse populations. METHODS: Chinese, Polish, Russian, and US population-based samples were studied. The relationship between cholesterol levels and mortality was assessed by Cox proportional hazard regression with restricted piecewise cubic splines. RESULTS: The cholesterol and total mortality relationship was statistically significantly J-shaped for all men combined. In country-specific relationships, cholesterol was significantly, linearly, and positively related to total mortality in Russian and US men. For women, the relationship was non-linear, but not statistically significant, and became statistically significant upon adjustment for other risk factors. For Polish women, a statistically significant inverse relationship existed. CHD mortality and cardiovascular disease (CVD) mortality increased linearly with cholesterol in Polish, Russian, and US men and the aggregate of men, but there was no relationship for women. Cancer mortality was not related to cholesterol except for the Polish cohort and Russian women, where there was an inverse relationship. CONCLUSIONS: Serum cholesterol was a strong, consistent predictor of CHD and CVD mortality in Polish, Russian, and US men despite their social diversity. In contrast to CHD mortality, the relation of cholesterol to total mortality and non-CVD mortality varied by country and gender.