Design of Mn-based nanozymes with multiple enzyme-like activities for identification/quantification of glyphosate and green transformation of organophosphorus.

A Mn-based nanozyme, Mn-uNF/Si, with excellent alkali phosphatase-like activity was designed by in-situ growth of ultrathin Mn-MOF on the surface of silicon spheres, and implemented as an effective solid Lewis-Brønsted acid catalyst for broad-spectrum dephosphorylation. H218O-mediated GC-MS studies confirmed the cleavage sites and the involvement of H2O in the new bonds. DRIFT NH3-IR and in-situ ATR-FTIR confirmed the coexistence of Lewis-Brønsted acid sites and the adjustment of adsorption configurations at the interfacial sites. In addition, a green transformation route of "turning waste into treasure" was proposed for the first time ("OPs→PO43-→P food additive") using edible C. reinhardtii as a transfer station. By alkali etching of Mn-uNF/Si, a nanozyme Mn-uNF with laccase-like activity was obtained. Intriguingly, glyphosate exhibits a laccase-like fingerprint-like response (+,-) of Mn-uNF, and a non-enzyme amplified sensor was thus designed, which shows a good linear relationship with Glyp in a wide range of 0.49-750 µM, with a low LOD of 0.61 µM, as well as high selectivity and anti-interference ability under the co-application of phosphate fertilizers and multiple pesticides. This work provides a controllable methodology for the design of bifunctional nanozymes, which sheds light on the highly efficient green transformation of OPs, and paves the way for the selective recognition and quantification of glyphosate. Mechanistically, we also provided deeper insights into the structure-activity relationship at the atomic scale.

m6A-mediated lnc-OXAR promotes oxaliplatin resistance by enhancing Ku70 stability in non-alcoholic steatohepatitis-related hepatocellular carcinoma.

BACKGROUND: The escalating prevalence of metabolic diseases has led to a rapid increase in non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (NASH-HCC). While oxaliplatin (OXA)-based hepatic arterial infusion chemotherapy (HAIC) has shown promise in advanced-stage HCC patients, its efficacy in NASH-HCC remains uncertain. This study aims to assess the effectiveness of OXA-based HAIC and elucidate the mechanisms underlying OXA resistance in NASH-HCC. METHODS: The key lncRNAs were screened through RNA-seq analysis of NASH/non-NASH and OXA-sensitive/OXA-resistant (OXA-S/R) HCC tissues. The biological functions of the lnc-OXAR (OXA resistance-related lncRNA in NASH-HCC) in NASH-HCC were verified through a series of in vitro and in vivo experiments. The molecular mechanism of lnc-OXAR was elucidated by fluorescence in situ hybridization, immunoprecipitation-mass spectrometry (FISH), Immunoprecipitation-Mass Spectrometry (IP-MS), RNA pulldown, RNA immunoprecipitation (RIP), methylated RNA immunoprecipitation sequencing (MeRIP-Seq) and a dual-luciferase reporter assay. RESULTS: NASH-HCC exhibited reduced responsiveness to OXA-based HAIC compared to non-NASH HCC. We identified and validated a novel transcript namedlnc-OXAR, which played a crucial role in conferring OXA resistance to NASH-HCC. Inhibition of lnc-OXAR suppressed HCC cell growth and restored OXA sensitivity both in NASH-HCC mouse models and in vitro. Mechanistically, lnc-OXAR recruited Ku70 and cystatin A (CSTA), preventing Ku70 degradation and facilitating DNA double-strand break (DSB) repair, thereby promoting OXA resistance in NASH-HCC. Additionally, WTAP-mediated m6A modification enhanced the stability of lnc-OXAR in an IGF2BP2-dependent manner. Notably, silencing lnc-OXAR significantly enhanced the response to OXA in patient-derived xenograft (PDX) models derived from NASH-HCC. CONCLUSIONS: The reduced responsiveness of NASH-HCC to OXA treatment can be attributed to the upregulation of lnc-OXAR. Our findings provide a rationale for stratifying HCC patients undergoing OXA-based HAIC based on etiology. Lnc-OXAR holds promise as a novel target for overcoming OXA resistance in NASH-HCC and improving prognosis.

KLF4 Suppresses the Progression of Hepatocellular Carcinoma by Reducing Tumor ATP Synthesis through Targeting the Mir-206/RICTOR Axis.

To address the increased energy demand, tumor cells undergo metabolic reprogramming, including oxidative phosphorylation (OXPHOS) and aerobic glycolysis. This study investigates the role of Kruppel-like factor 4 (KLF4), a transcription factor, as a tumor suppressor in hepatocellular carcinoma (HCC) by regulating ATP synthesis. Immunohistochemistry was performed to assess KLF4 expression in HCC tissues. Functional assays, such as CCK-8, EdU, and colony formation, as well as in vivo assays, including subcutaneous tumor formation and liver orthotopic xenograft mouse models, were conducted to determine the impact of KLF4 on HCC proliferation. Luciferase reporter assay and chromatin immunoprecipitation assay were utilized to evaluate the interaction between KLF4, miR-206, and RICTOR. The findings reveal low KLF4 expression in HCC, which is associated with poor prognosis. Both in vitro and in vivo functional assays demonstrate that KLF4 inhibits HCC cell proliferation. Mechanistically, it was demonstrated that KLF4 reduces ATP synthesis in HCC by suppressing the expression of RICTOR, a core component of mTORC2. This suppression promotes glutaminolysis to replenish the TCA cycle and increase ATP levels, facilitated by the promotion of miR-206 transcription. In conclusion, this study enhances the understanding of KLF4's role in HCC ATP synthesis and suggests that targeting the KLF4/miR-206/RICTOR axis could be a promising therapeutic approach for anti-HCC therapeutics.

The Cost-Effectiveness of an Advanced Hybrid Closed-Loop System Compared to Standard Management of Type 1 Diabetes in a Singapore Setting.

Background: Despite advances in technology, glycemic outcomes in people with type 1 diabetes (T1D) remain suboptimal. The MiniMed 780G (MM780G) advanced hybrid closed-loop (AHCL) system is the latest technology for T1D management with established safety and efficacy. This study explores the cost-effectiveness of MM780G AHCL compared against multiple daily injections (MDI) plus intermittently scanned continuous glucose monitor (isCGM). Methods: A cost-utility analysis was conducted, simulating lifetime outcomes for 1000 T1D individuals, with baseline hemoglobin A1c of 8.4%, using the IQVIA Core Diabetes Model (CDM) v9.5. A Singapore health care payer perspective was taken with 2023 costs applied. Treatment effects were taken from the ADAPT study and treatment-related events from a combination of sources. T1D complication costs were derived from local literature, and health state utilities and disutilities from published literature. Scenario analyses and probabilistic sensitivity analyses (PSAs) explored uncertainty. Cost-effectiveness was assessed based on willingness-to-pay (WTP) thresholds set to Singapore Dollars (SGD) 45,000 (United States Dollars [USD] 33,087) per quality-adjusted life year (QALY) and Singapore's gross domestic product (GDP) per capita of SGD 114,165 (USD 83,941) per QALY. Results: A switch from MDI plus isCGM to MM780G resulted in expected gains in life-years (+0.78) and QALYs (+1.45). Cost savings through reduction in T1D complications (SGD 25,465; USD 18,723) partially offset the higher treatment costs in the AHCL arm (+SGD 74,538; +USD 54,805), resulting in an estimated incremental cost-effectiveness ratio of SGD 33,797 (USD 24,850) per QALY gained. Findings were robust, with PSA outputs indicating 81% and 99% probabilities of cost-effectiveness at the stated WTP thresholds. Conclusion: MM780G is a cost-effective option for people with T1D managed in a Singapore setting.

RFX6 facilitates aerobic glycolysis-mediated growth and metastasis of hepatocellular carcinoma through targeting PGAM1.

BACKGROUND: Hepatocellular carcinoma (HCC) cells undergo reprogramming of glucose metabolism to support uncontrolled proliferation, of which the intrinsic mechanism still merits further investigation. Although regulatory factor X6 (RFX6) is aberrantly expressed in different cancers, its precise role in cancer development remains ambiguous. METHODS: Microarrays of HCC tissues were employed to investigate the expression of RFX6 in tumour and adjacent non-neoplastic tissues. Functional assays were employed to explore the role of RFX6 in HCC development. Chromatin immunoprecipitation, untargeted metabolome profiling and sequencing were performed to identify potential downstream genes and pathways regulated by RFX6. Metabolic assays were employed to investigate the effect of RFX6 on glycolysis in HCC cells. Bioinformatics databases were used to validate the above findings. RESULTS: HCC tissues exhibited elevated expression of RFX6. High RFX6 expression represented as an independent hazard factor correlated to poor prognosis in patients with HCC. RFX6 deficiency inhibited HCC development in vitro and in vivo, while its overexpression exerted opposite functions. Mechanistically, RFX6 bound to the promoter area of phosphoglycerate mutase 1 (PGAM1) and upregulated its expression. The increased PGAM1 protein levels enhanced glycolysis and further promoted the development of HCC. CONCLUSIONS: RFX6 acted as a novel driver for HCC development by promoting aerobic glycolysis, disclosing the potential of the RFX6-PGAM1 axis for therapeutic targeting.

Dysregulation of PLOD2 Promotes Tumor Metastasis and Invasion in Hepatocellular Carcinoma.

Background and Aims: Metastasis is a major factor associated with high recurrence and mortality in hepatocellular carcinoma (HCC) patients while the underlying mechanism of metastasis remains elusive. In our study, procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) was shown to be involved in the process of metastasis in HCC. Methods: The Cancer Genome Atlas (TCGA) database and HCC tissue microarrays were used to evaluate the expression of genes. In vitro migration, invasion, in vivo subcutaneous tumor model and in vivo lung metastasis assays were used to determine the role of PLOD2 in tumor growth and metastasis in HCC. RNA sequencing and gene set enrichment analysis were performed to uncover the downstream factor of PLOD2 in HCC cells. A luciferase reporter assay was performed to evaluate the interaction between PLOD2 and interferon regulatory factor 5 (IRF5). Results: The expression of PLOD2 in HCC tissues was higher than that in adjacent tissues, and increased PLOD2 expression was often found in advanced tumors and was correlated with poor prognosis in HCC patients. In vitro experiments, knockdown of PLOD2 reduced the migration and invasion of human HCC cells. Loss of PLOD2 suppressed human HCC growth and metastasis in a subcutaneous tumor model and a lung metastasis model. Baculoviral IAP repeat containing 3 (BIRC3) was proven to be the downstream factor of PLOD2 in human HCC cells. In addition, PLOD2 was transcriptionally regulated by IRF5 in HCC cells. Conclusions: High expression of PLOD2 was regulated by IRF5, which was correlated with the poor survival of HCC patients. PLOD2 enhanced HCC metastasis via BIRC3, suggesting that PLOD2 might be a valuable prognostic biomarker for HCC treatment.

PRMT3-mediated arginine methylation of IGF2BP1 promotes oxaliplatin resistance in liver cancer.

Although oxaliplatin-based chemotherapy has been effective in the treatment of hepatocellular carcinoma (HCC), primary or acquired resistance to oxaliplatin remains a major challenge in the clinic. Through functional screening using CRISPR/Cas9 activation library, transcriptomic profiling of clinical samples, and functional validation in vitro and in vivo, we identify PRMT3 as a key driver of oxaliplatin resistance. Mechanistically, PRMT3-mediated oxaliplatin-resistance is in part dependent on the methylation of IGF2BP1 at R452, which is critical for the function of IGF2BP1 in stabilizing the mRNA of HEG1, an effector of PRMT3-IGF2BP1 axis. Also, PRMT3 overexpression may serve as a biomarker for oxaliplatin resistance in HCC patients. Collectively, our study defines the PRTM3-IGF2BP1-HEG1 axis as important regulators and therapeutic targets in oxaliplatin-resistance and suggests the potential to use PRMT3 expression level in pretreatment biopsy as a biomarker for oxaliplatin-resistance in HCC patients.

PLK1-mediated phosphorylation of PPIL2 regulates HR via CtIP.

Homologous recombination (HR) is an error-free DNA double-strand break (DSB) repair pathway, which safeguards genome integrity and cell viability. Human C-terminal binding protein (CtBP)-interacting protein (CtIP) is a central regulator of the pathway which initiates the DNA end resection in HR. Ubiquitination modification of CtIP is known in some cases to control DNA resection and promote HR. However, it remains unclear how cells restrain CtIP activity in unstressed cells. We show that the ubiquitin E3 ligase PPIL2 is recruited to DNA damage sites through interactions with an HR-related protein ZNF830, implying PPIL2's involvement in DNA repair. We found that PPIL2 interacts with and ubiquitinates CtIP at the K426 site, representing a hereunto unknown ubiquitination site. Ubiquitination of CtIP by PPIL2 suppresses HR and DNA resection. This inhibition of PPIL2 is also modulated by phosphorylation at multiple sites by PLK1, which reduces PPIL2 ubiquitination of CtIP. Our findings reveal new regulatory complexity in CtIP ubiquitination in DSB repair. We propose that the PPIL2-dependent CtIP ubiquitination prevents CtIP from interacting with DNA, thereby inhibiting HR.

S100A9 Derived from Chemoembolization-Induced Hypoxia Governs Mitochondrial Function in Hepatocellular Carcinoma Progression.

Transarterial chemoembolization (TACE) is the major treatment for advanced hepatocellular carcinoma (HCC), but it may cause hypoxic environment, leading to rapid progression after treatment. Here, using high-throughput sequencing on different models, S100 calcium binding protein A9 (S100A9) is identified as a key oncogene involved in post-TACE progression. Depletion or pharmacologic inhibition of S100A9 significantly dampens the growth and metastatic ability of HCC. Mechanistically, TACE induces S100A9 via hypoxia-inducible factor 1α (HIF1A)-mediated pathway. S100A9 acts as a scaffold recruiting ubiquitin specific peptidase 10 and phosphoglycerate mutase family member 5 (PGAM5) to form a tripolymer, causing the deubiquitination and stabilization of PGAM5, leading to mitochondrial fission and reactive oxygen species production, thereby promoting the growth and metastasis of HCC. Higher S100A9 level in HCC tissue or in serum predicts a worse outcome for HCC patients. Collectively, this study identifies S100A9 as a key driver for post-TACE HCC progression. Targeting S100A9 may be a promising therapeutic strategy for HCC patients.

Preparation and SERS performance of silver nanowires arrays on paper by automatic writing method.

Silver nanowire ink was written on the surface of drawing paper by automatic writing method. Scanning electron microscopy was used to characterize the surface morphologies of the drawing paper before and after writing silver nanowires. The effects of fabrication parameters and measurement parameters on silver nanowires arrays were investigated. Crystal violet was selected as the probe molecule to study the SERS performance of silver nanowires arrays. The detection limit of crystal violet was as low as 10-15 mol/L. The uniformity and repeatability of the arrays were also explored, and the relative standard deviation values were about 10%. Moreover, silver nanowires arrays were also relatively stable that SERS signals were still observed after ten weeks. Detection of the crystal violet residue was further achieved on the substrates by continuously pressing nine times. In addition, silver nanowires arrays were also applied to the quantitative analyses of 2, 2'-bipyridyl.

A detailed assessment of liver function in patients with hepatocellular carcinoma via the modified albumin-bilirubin (mALBI) grade.

Recently, the albumin-bilirubin (ALBI) score, a continuous index consisting of only albumin and bilirubin, has been developed for objectively assessing liver function in patients with hepatocellular carcinoma (HCC). However, the ALBI score was arbitrarily categorized into three ALBI grades based on two artificially predetermined cutoff points with no explanation and statistical grounds, causing a considerable loss of discriminatory ability. This study aims to propose a modified ALBI (mALBI) grade for offering a detailed evaluation of hepatic reserve and specify its role during clinical practice in the HCC setting. The study population comprised 3540 HCC patients treated with mainstream therapies including hepatectomy (n=2056), thermal ablation (n=550), and transcatheter arterial chemoembolization (n=934) from 2002 to 2017. The ALBI score was stratified into four mALBI grades through a recently proposed statistical method aiming to select the optimal cutoff points of a continuous predictive variable by maximizing the discriminative ability in a multivariable Cox regression model. The mALBI grade had an overall better discriminatory ability than the ALBI grade in predicting overall survival through Harrell's C-index (0.614 vs. 0.598, P<0.001). Both visual inspections of Kaplan-Meier curves and calculation of hazard ratios displayed a more subtle evaluation of liver function using the mALBI grade. Moreover, the newly identified cut-point (ALBI score = -2.29) between the mALBI grade 2a and 2b was much closer to a 30% retention rate of indocyanine green at 15 minutes, an indicator for the performance of a subsegmentectomy. The newly proposed mALBI grade provides a more subtle assessment of liver function to guide clinical decision-making and predicts the prognosis of HCC patients more accurately than the original ALBI grade.

Insufficient ablation induces E3-ligase Nedd4 to promote hepatocellular carcinoma progression by tuning TGF-ß signaling.

Thermal ablation is a main curative therapy for early-stage hepatocellular carcinoma (HCC). However, insufficient ablation has been shown to promote HCC progression. E3 ligases have been approved to play important roles in malignant tumors. Whether E3 ligases are involved in HCC progression caused by insufficient ablation remains unclear. Herein, using RNA-sequencing coupled with an in vitro loss-of-function screen, we found that the E3 ligase Neuronal Precursor cell-expressed Developmentally Downregulated 4 (Nedd4) was upregulated in HCC insufficient ablation tissues and promoted HCC cells migration. The upregulation of Nedd4 was induced by METTL14-mediated N6-methyladenosine modification after sublethal heat treatment. Knockdown of Nedd4 inhibited HCC metastasis and growth in vitro and in vivo. Mechanistically, Nedd4 enhanced TGF-ß signal transduction mediated tumor progression by directly binding to TGF-ß type I receptor (TGFBR1) and forming K27-linked ubiquitin at Lysine 391. Additionally, the adverse effect on HCC of sublethal heat treatment was mediated by Nedd4. Clinically, high Nedd4 expression was positively correlated with aggressive tumor phenotypes and poor prognosis in HCC patients. Patient-derived xenograft (PDX) model confirmed this conclusion. Collectively, this study demonstrated that Nedd4 induced by insufficient ablation plays a crucial role in promoting HCC progression and provides a novel therapeutic target for HCC.

Factors associated with adherence to colonoscopy among individuals who were positive in the preliminary screening for colorectal neoplasms.

OBJECTIVES: This study aimed to investigate the potential factors associated with adherence to colonoscopy among participants who were preliminarily screened positive in a community-based colorectal cancer screening program in China. METHODS: This study analyzed data from 1219 out of 6971 community residents who were identified as positive cases by the well-validated high-risk factor questionnaire (HRFQ) or fecal immunochemical test (FIT) in the preliminary screening stage for colorectal neoplasms. Patients showing adherence to colonoscopy were defined as those who received positive results in a preliminary screening for colorectal neoplasms and later received a colonoscopy examination as required. The associations of social-demographic factors, lifestyle behaviors, history of diabetes, body mass index (BMI), and risk factors in the HRFQ with adherence to colonoscopy were evaluated using logistic regression models. RESULTS: Among 1219 participants who preliminarily screened positive, the top five risk factors reported by the participants were chronic constipation (25.9%), hematochezia (23.5%), family history of CRC in first-degree relatives (22.1%), chronic diarrhea (21.8%), and history of polyps (16.6%). Around 14.2% of participants who preliminarily screened positive reported three or more risk factors, and the proportion was 26.2% among participants who were positive according to both HRFQ and FIT. Among all participants who were preliminarily screened positive, the multivariable results showed that those who were married (OR = 1.58, 95% CI: 1.12, 2.25, p = 0.01), had chronic diarrhea (OR = 1.34, 95% CI: 1.00, 1.78, p = 0.047), and had a positive FIT (OR = 1.60, 95% CI: 1.21, 2.10, p < 0.001 for patients who were negative according to HRFQ but positive according to FIT; OR = 2.12, 95% CI: 1.33, 2.78, p = 0.002 for patients who were positive for both HRFQ and FIT) were more likely to adhere to colonoscopy, while participants with a history of cancer (OR: 0.50, 95% CI: 0.31, 0.79, p = 0.003) were less likely to adhere to colonoscopy. The results among participants who were tested positive according to only HRFQ were similar to those among all participants who were tested positive according to HRFQ or FIT. However, among participants who were tested positive according to only FIT, we only found that those who were married (OR = 2.52, 95% CI: 1.08, 5.90, p = 0.033) had a higher odds of adhering to colonoscopy, while those with a history of diabetes (OR = 0.35, 95% CI: 0.13, 0.96, p = 0.042) were less likely to adhere to colonoscopy. CONCLUSION: Our findings provide evidence supporting the development of tailored interventional strategies that aim to improve adherence to colonoscopy for individuals with a high risk of colorectal neoplasms. Both barriers and facilitators associated with adherence to colonoscopy should be considered in supportive systems and health policies. However, further well-designed prospective studies are warranted to confirm our findings.

Factors associated with positive predictive value of preliminary screening in a two-step screening strategy for colorectal neoplasms in China.

BACKGROUND: The positive predictive value (PPV) of high risk factor questionnaire (HRFQ) plus fecal immunochemical test (FIT) as preliminary screening strategy for colorectal-related neoplasia is relatively low. We aim to explore independent factors associated with PPVs of HRFQ combined FIT for selecting high risk individuals for colonoscopy. METHODS: A total of 6971 residents were enrolled in a community-based screening program. Participants who had positive results of HRFQ and/or FIT and subsequently received colonoscopy were involved. The associations of socio-demographic factors, lifestyle behaviors, and high risk factors of colorectal cancer with PPVs of HRFQ, FIT, and their combination were evaluated by multivariable logistic regression models. RESULTS: Among 572 involved cases, 249 (43.5%) colorectal neoplasms were detected by colonoscopy, including 71 advanced adenoma (12.4%) and 9 colorectal cancer (CRC) (1.6%). The PPVs of preliminary screening were 43.5% for total colorectal neoplasms, 14.0% for advanced neoplasm, and 1.6% for CRC. Adding positive HRFQ to FIT could improve the PPV from 3.5 to 8.0% for detecting CRC. Preliminarily screened positive individuals who were males [adjusted odds ratio (AOR): 1.95, 95% CI 1.31, 2.90; p < 0.001], elders (> 60 years) (AOR: 1.70, 95% CI 1.17, 2.46; p = 0.005), or ex-/current smokers (AOR: 3.04, 95% CI 1.31, 7.09; p = 0.10) had higher odds of PPVs of detecting colorectal neoplasms. CONCLUSIONS: Combining HRFQ and FIT could largely improve PPVs for screening advanced neoplasm and CRC. Gender and age-specific FIT cut-off values as well as initiating ages for CRC screening might be recommended to improve the accuracy and effectiveness of current screening algorithm.

YdfD, a Lysis Protein of the Qin Prophage, Is a Specific Inhibitor of the IspG-Catalyzed Step in the MEP Pathway of Escherichia coli.

Bacterial cryptic prophage (defective prophage) genes are known to drastically influence host physiology, such as causing cell growth arrest or lysis, upon expression. Many phages encode lytic proteins to destroy the cell envelope. As natural antibiotics, only a few lysis target proteins were identified. ydfD is a lytic gene from the Qin cryptic prophage that encodes a 63-amino-acid protein, the ectopic expression of which in Escherichia coli can cause nearly complete cell lysis rapidly. The bacterial 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway is responsible for synthesizing the isoprenoids uniquely required for sustaining bacterial growth. In this study, we provide evidence that YdfD can interact with IspG, a key enzyme involved in the MEP pathway, both in vivo and in vitro. We show that intact YdfD is required for the interaction with IspG to perform its lysis function and that the mRNA levels of ydfD increase significantly under certain stress conditions. Crucially, the cell lysis induced by YdfD can be abolished by the overexpression of ispG or the complementation of the IspG enzyme catalysis product methylerythritol 2,4-cyclodiphosphate. We propose that YdfD from the Qin cryptic prophage inhibits IspG to block the MEP pathway, leading to a compromised cell membrane and cell wall biosynthesis and eventual cell lysis.

Pan-Cancer Analysis of IGF-1 and IGF-1R as Potential Prognostic Biomarkers and Immunotherapy Targets.

AIM: Insulin-like growth factor-1 receptor (IGF-1R) is one of the main members of the tyrosine protein kinase receptor family. This receptor binds insulin-like growth factor-1 (IGF-1) with a high affinity. IGF-1 is a member of a family of proteins involved in mediating growth and development. However, the correlations of IGF-1 and IGF-1R to prognosis and tumor-infiltrating lymphocytes in different cancers remain unclear. METHOD: This research comprehensively analyzed the expression pattern of IGF-1 and IGF-1R and the influence of IGF-1 and IGF-1R on clinical significance in prognosis prediction among 33 types of malignancies using The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE) databases. The correlation between IGF-1, IGF-1R, and cancer immunity was explored. RESULTS: IGF-1 and IGF-1R displayed inconsistent gene expression levels among diverse cancer cell lines. Typically, high expression level of IGF-1 and IGF-1R was detected in most malignant tumors. High expression of IGF-1 was closely bound up with the unfavorable overall survival (OS) for patients in BLCA, CHOL, and LAML upon Cox and Kaplan-Meier analyses. While high expression of IGF-1R was closely bound up with the unfavorable overall survival (OS) for patients in BLCA, LIHC, and LUAD. Furthermore, high expression level of IGF-1 and IGF-1R were closely connected with high degrees of tumor infiltrates, including CD4+ T cell, dendritic cells, and macrophages. In addition, we found that IGF-1 was commonly positively correlated with the expression of gene markers including LAIR1, ICOS, CD40LG, CTLA4, CD48, CD28, CD200R1, HAVCR2, and CD86. Whereas, IGF-1R was commonly positively correlated with the expression of gene markers including NRP1 and CD276. More importantly, IGF-1 and IGF-1R expression were correlated with tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MMR), and DNA methyltransferase (DNMT) of different types of cancers. CONCLUSIONS: The impact of high IGF-1 and IGF-1R on prognosis and immune infiltrates differs across cancer types. Anti-IGF-1R therapy may inhibit tumor growth and contribute to immunotherapy in LIHC and KIRC.

Transarterial chemoembolization (TACE) combined with apatinib versus TACE combined with sorafenib in advanced hepatocellular carcinoma patients: a multicenter retrospective study.

BACKGROUND: The combination of transarterial chemoembolization (TACE) with sorafenib has demonstrated superior efficacy over sorafenib and TACE monotherapy in hepatocellular carcinoma (HCC). Apatinib, a new targeted agent, has been recently reported to prolong the survival of HCC patients, either alone or in combination with TACE. However, the superior regimen between TACE-apatinib and TACE-sorafenib in HCC patients has not been determined. In this study, we compared the efficacy and safety of TACE-apatinib versus TACE-sorafenib in advanced stage HCC patients. METHODS: The data of 201 HCC patients who had received TACE-sorafenib or TACE-apatinib between January 2016 and June 2018 in three hospitals were retrospectively reviewed. Overall survival (OS), progression-free survival (PFS), and adverse effects (AEs) between the two treatment groups were compared. A subgroup analysis based on the doses of targeted agents was also performed. RESULTS: No significant differences in baseline clinicopathological features were found between the two groups except for dose reduction. The TACE-apatinib group had higher incidences of hypertension, oral or anal ulcer and proteinuria, while the TACE-sorafenib group had higher incidences of diarrhea and alopecia. Grade 3/4 AEs occurred more frequently in the TACE-apatinib group than in the TACE-sorafenib group (52.3% vs. 22.6%, P<0.001). The TACE-sorafenib group had better PFS than the TACE-apatinib group (median PFS: 5.0 vs. 6.0 months, P=0.002) while the two groups showed no difference in OS (median OS: 13.0 vs. 13.0 months, P=0.448). The TACE-apatinib group had a higher rate of targeted agent dose reduction than the TACE-sorafenib group (53.5% vs. 17.4%, P<0.001). When the patients were stratified into normal and reduced-dose subgroups, those who received TACE-sorafenib exhibited improved PFS but similar OS compared with the patients who received TACE-apatinib in the reduced-dose subgroup (median OS: 12.0 vs. 13.3 months, P=0.614; median PFS: 3.0 vs. 7.0 months, P<0.001). Multivariable analysis validated that treatments and dose reduction were independent prognostic factors for PFS among all patients. CONCLUSIONS: Compared with TACE-sorafenib, the strategy of TACE-apatinib yielded shorter PFS in advanced HCC patients while no difference in OS was observed. A high rate of AE-related dose reduction of apatinib could account for the observed differences.

Gender Differences in Factors Associated with Clinically Meaningful Weight Loss among Adults Who Were Overweight or Obese: A Population-Based Cohort Study.

OBJECTIVES: The impact of heterogeneity on gender difference for achieving clinically meaningful weight loss (cmWL) remains unclear. Here, we explored the potential gender differences in factors associated with cmWL. METHODS: A total of 60,668 participants with body mass index (BMI) ≥25 kg/m2 at study entry and available BMI values at follow-up were included in this study. cmWL was defined as a weight loss of ≥5% from the study entry to follow-up. The associations of social-demographic factors, personal history of chronic diseases, lifestyle behaviors, and history of BMI with cmWL were evaluated using logistic regression models. RESULTS: During a median follow-up of 9.13 years, 26.6% of the participants had a cmWL (30.8% for females vs. 23.1% in males; p < 0.001). Participants with older age, obesity at study entry, being more physical activity compared to 10 years ago, being relapsed smokers or consistent current smokers, having a history of chronic diseases (i.e., diabetes, osteoporosis, and stroke), cancer diagnosis during the study period, and more than 10-year follow-up were more likely to achieve cmWL in both males and females (all p < 0.05). The new smoking quitters and participants with less active in physical activity compared to 10 years ago were less likely to achieve cmWL in both males and females (all p < 0.05). Specifically, males with a history of emphysema were more likely to reach cmWL, and for females, those being overweight at 20 years old and current drinkers were more likely to reach cmWL (p < 0.05). Sensitivity analyses demonstrated similar results. CONCLUSION: Age, BMI status, physical activity, smoking status, family income, and health status were independent factors in males and females for weight management. However, further well-designed prospective studies are warranted to confirm our findings.

Conversion to Resectability Using Transarterial Chemoembolization Combined With Hepatic Arterial Infusion Chemotherapy for Initially Unresectable Hepatocellular Carcinoma.

Objective: To evaluate whether this conversion rate to resectability could be increased when patients are treated with transarterial chemoembolization and hepatic arterial infusion chemotherapy (TACE-HAIC) using oxaliplatin plus fluorouracil/leucovorin. Background: Conventional TACE (c-TACE) is a common regimen for initially unresectable hepatocellular carcinoma (HCC), which converts to curative-intent resection in about 10% of those patients. It is urgent need to investigated better regimen for those patients. Methods: The data of 83 initially unresectable HCC patients were examined, including 41 patients in the TACE-HAIC group and 42 patients in the c-TACE group. Their response rate, conversion rate to resection, survival outcome, and adverse events were compared. Results: The conversion rate was significantly better in the TACE-HAIC group than in the c-TACE group (48.8% vs 9.5%; P < 0.001). The TACE-HAIC had marginal superiority in overall response rate as compared to c-TACE (14.6% vs 2.4%; P = 0.107 [RECIST]; 65.9% vs 16.7%; P < 0.001 [mRECIST], respectively). The median progression-free survival was not available and 9.2 months for the TACE-HAIC and cTACE groups, respectively (hazard rate [HR]: 0.38; 95% confidence interval [CI], 0.20-0.70; P = 0.003). The median overall survival was not available and 13.5 months for the TACE-HAIC and c-TACE groups, respectively (HR, 0.63; 95% CI, 0.34-1.17; P = 0.132). The 2 groups had similar rates of grade 3/4 adverse events (all P > 0.05). Conclusions: TACE-HAIC demonstrated a higher conversion rate and progression-free survival benefit than c-TACE and could be considered as a more effective regimen for patients with initially unresectable HCC. Future prospective randomized trials are needed to confirm it.

Transarterial chemoembolization combined with apatinib versus transarterial chemoembolization alone for hepatocellular carcinoma with macroscopic vascular invasion: A propensity score matching analysis.

CONTEXT: Macroscopic vascular invasion in hepatocellular carcinoma (HCC) remains challenging to treat. AIMS: The aim of this study was to compare the efficacy of transarterial chemoembolization (TACE)-apatinib therapy with TACE treatment alone in HCC patients with macrovascular invasion, using propensity score matching (PSM). SETTINGS AND DESIGN: Matched paired comparison between the TACE-apatinib and TACE alone group using 1:2 PSM was utilized. SUBJECTS AND METHODS: Between 2013 and 2019, 378 patients receiving TACE-apatinib or TACE alone were included based on specific selection criteria. STATISTICAL ANALYSIS USED: Multivariate Cox regression models were used to determine the independent prognostic factors for overall survival (OS). RESULTS: Of the patients included, 40 (12.5%) received TACE-apatinib treatment and 280 (87.5%) received TACE alone. Tumor sizes of patients in the TACE-apatinib group were more frequently classified as small (<5 cm) compared to those in the TACE alone group (P = 0.021; mean: 8.6 cm vs. 10.2 cm). After 1:2 PSM, 40 pairs of HCC patients with well-matched covariates were selected from the two treatment groups. Patients in the TACE-apatinib group had higher OS rates than patients in the TACE alone group (P = 0.018). The median OS times were 18.2 and 8.5 months in the TACE-apatinib and TACE alone groups, respectively. The OS hazard ratio for the choice of TACE-apatinib treatment compared to TACE treatment alone was 0.50 (95% confidence interval: 0.28-0.90; P = 0.021). CONCLUSIONS: TACE combined with apatinib may result in superior OS compared to TACE therapy alone for HCC patients with macrovascular invasion.