YTHDF1 promotes gallbladder cancer progression via post-transcriptional regulation of the m6A/UHRF1 axis.

Gallbladder cancer is a rare but fatal malignancy. However, the mechanisms underlying gallbladder carcinogenesis and its progression are poorly understood. The function of m6A modification and its regulators was still unclear for gallbladder cancer. The current study seeks to investigate the function of YTH m6A RNA-binding protein 1 (YTHDF1) in gallbladder cancer. Transcriptomic analysis and immunochemical staining of YTHDF1 in gallbladder cancer tissues revealed its upregulation compared to paracancerous tissues. Moreover, YTHDF1 promotes the proliferation assays, Transwell migration assays, and Transwell invasion assays of gallbladder cancer cells in vitro. And it also increased tumour growth in xenograft mouse model and metastases in tail vein injection model in vivo. In vitro, UHRF1 knockdown partly reversed the effects of YTHDF1 overexpression. Mechanistically, dual-luciferase assays proved that YTHDF1 promotes UHRF1 expression via direct binding to the mRNA 3'-UTR in a m6A-dependent manner. Overexpression of YTHDF1 enhanced UHRF1 mRNA stability, as demonstrated by mRNA stability assays, and Co-IP studies confirmed a direct interaction between YTHDF1 and PABPC1. Collectively, these findings provide new insights into the progression of gallbladder cancer as well as a novel post-transcriptional mechanism of YTHDF1 via stabilizing target mRNA.

M6A RNA methylation in biliary tract cancer: the function roles and potential therapeutic implications.

Biliary tract cancers (BTCs) are relatively rare malignancies with a poor prognosis. For advanced BTCs, the efficacy of current chemotherapeutic approaches is limited. Consequently, there is an urgent need to deepen our understanding of the molecular mechanisms underlying BTC tumorigenesis and development for the exploration of effective targeted therapies. N6-methyladenosine (m6A), the most abundant RNA modifications in eukaryotes, is found usually dysregulated and involved in tumorigenesis, progression, and drug resistance in tumors. Numerous studies have confirmed that aberrant m6A regulators function as either oncogenes or tumor suppressors in BTCs by the reversible regulation of RNA metabolism, including splicing, export, degradation and translation. In this review, we summarized the current roles of the m6A regulators and their functional impacts on RNA fate in BTCs. The improved understanding of m6A modification in BTCs also provides a reasonable outlook for the exploration of new diagnostic strategies and efficient therapeutic targets.

Radiomics-based machine learning and deep learning to predict serosal involvement in gallbladder cancer.

OBJECTIVE: Our study aimed to determine whether radiomics models based on contrast-enhanced computed tomography (CECT) have considerable ability to predict serosal involvement in gallbladder cancer (GBC) patients. MATERIALS AND METHODS: A total of 152 patients diagnosed with GBC were retrospectively enrolled and divided into the serosal involvement group and no serosal involvement group according to paraffin pathology results. The regions of interest (ROIs) in the lesion on all CT images were drawn by two radiologists using ITK-SNAP software (version 3.8.0). A total of 412 features were extracted from the CT images of each patient. The Mann‒Whitney U test was applied to identify features with significant differences between groups. Seven machine learning algorithms and a deep learning model based on fully connected neural networks (f-CNNs) were used for radiomics model construction. The prediction efficacy of the models was evaluated using receiver operating characteristic (ROC) curve analysis. RESULTS: Through the Mann‒Whitney U test, 75 of the 412 features extracted from the CT images of patients were significantly different between groups (P < 0.05). Among all the algorithms, logistic regression achieved the highest performance with an area under the curve (AUC) of 0.944 (sensitivity 0.889, specificity 0.8); the f-CNN deep learning model had an AUC of 0.916, and the model showed high predictive power for serosal involvement, with a sensitivity of 0.733 and a specificity of 0.801. CONCLUSION: Radiomics models based on features derived from CECT showed convincing performances in predicting serosal involvement in GBC.

YTHDF2 promotes gallbladder cancer progression and gemcitabine resistance via m6A-dependent DAPK3 degradation.

N6-methyladenosine (m6A) is the most abundant internal modification in eukaryotic RNA and involved in the carcinogenesis of various malignancies. However, the functions and mechanisms of m6A in gallbladder cancer (GBC) remain unclear. In this study, we investigated the role and underlying mechanism of the RNA-binding protein YT521-B homology domain-containing family protein 2 (YTHDF2), an m6A reader, in GBC. Herein, we detected that YTHDF2 was remarkably upregulated in GBC tissues compared to normal gallbladder tissues. Functionally, YTHDF2 overexpression promoted the proliferation, tumor growth, migration, and invasion of GBC cells while inhibiting the apoptosis in vitro and in vivo. Conversely, YTHDF2 knockdown induced opposite results. Mechanistically, we further investigated the underlying mechanism by integrating RNA immunoprecipitation sequencing (RIP-seq), m6A-modified RIP-seq, and RNA sequencing, which revealed that death-associated protein kinase 3 (DAPK3) is a direct target of YTHDF2. YTHDF2 binds to the 3'-UTR of DAPK3 mRNA and facilitates its degradation in an m6A-dependent manner. DAPK3 inhibition restores the tumor-suppressive phenotype induced by YTHDF2 deficiency. Moreover, the YTHDF2/DAPK3 axis induces the resistance of GBC cells to gemcitabine. In conclusion, we reveal the oncogenic role of YTHDF2 in GBC, demonstrating that YTHDF2 increases the mRNA degradation of the tumor suppressor DAPK3 in an m6A-dependent way, which promotes GBC progression and desensitizes GBC cells to gemcitabine. Our findings provide novel insights into potential therapeutic strategies for GBC.

Tumor-derived covalent organic framework nanozymes for targeted chemo-photothermal combination therapy.

Covalent organic frameworks (COFs) have garnered enormous attention in anti-cancer therapy recently. However, the intrinsic drawbacks such as poor biocompatibility and low target-specificity greatly restrain the full clinical implementation of COF. Herein, we report a biomimetic multifunctional COF nanozyme, which consists of AIEgen-based COF (TPE-s COF) with encapsulated gold nanoparticles (Au NPs). The nanozyme was co-cultured with HepG2 cells until the cell membrane was fused with lipophilic TPE-s COF-Au@Cisplatin. By using the cryo-shocking method, we fabricated an inactivated form of the TPE-s COF-Au@Cisplatin nanozyme endocytosed in the HepG2 cell membrane (M@TPE-s COF-Au@Cisplatin), which lost their proliferative ability and pathogenicity. Upon laser irradiation, the M@TPE-s COF-Au@Cisplatin nanozymes cleaved, thereby releasing the TPE-s COF-Au nanozyme and Cisplatin to exert their photothermal and drug therapeutic effect. This work opens a new avenue to the synthesis of tumor-derived fluorescent TPE-s COF-Au nanozymes for highly efficient, synergetic, and targeted chemo-photothermal combination therapy of liver cancer.

Delivery of Small-Molecule Drugs and Protein Drugs by Injectable Acid-Responsive Self-Assembled COF Hydrogels for Combinatorial Lung Cancer Treatment.

Covalent organic frameworks (COFs) have revealed enormous application prospects for cancer therapeutics recently, but their assembly systems face considerable challenges, such as the codelivery of hydrophobic and hydrophilic protein drugs with different physicochemical properties for in vivo delivery and release, as well as endosomal/lysosomal escape of protein drugs. To address these issues, we leveraged the high specific surface area, lipotropism, and structural tunability of boronate ester-linked COFs (COF-1) for the construction of advanced drug delivery systems. We first encapsulated the small-molecule drug doxorubicin (DOX) into a lipophilic COF (COF-1@DOX) and immobilized the functional protein drug ribonuclease A (RNase A) on the surface of the COF (RNase A-COF-1@DOX). We then created a novel composite delivery system (RNase A-COF-1@DOX gel) by cross-linking an albumin-oxygenated hydrogel (gel) network into the pores of COFs, allowing targeted codelivery of protein and small-molecule drugs in vivo. Using in-living body and multichannel fluorescence imaging, we analyzed the in vivo codelivery of protein and small-molecule drugs in a Lewis lung carcinoma (LLC) model. Finally, we applied the RNase A-COF-1@DOX gel to treat lung cancer in mice. This study paves an avenue for constructing COF-based drug delivery systems for lung cancer treatment and holds the potential to be extended to other types of cancer for more effective and targeted therapeutic treatments.

Construction of a prognostic model for HCC based on ferroptosis-related lncRNAs expression and its potential to predict the response and irAEs of immunotherapy.

Background: Ferroptosis is an iron-dependent programmed cell death process, and studies have confirmed that it plays an important regulatory role in the occurrence and development of various malignancies including hepatocellular carcinoma (HCC). In addition, the role of abnormally expressed long non-coding RNAs (lncRNAs) in regulating and driving the occurrence and development of HCC has attracted more and more attention. However, there is still a lack of research on the role of ferroptosis-related lncRNAs in the prognosis prediction of HCC patients. Method: In this study, we used the Pearson test method to analyze the association between differentially expressed lncRNAs and ferroptosis-related genes in HCC and normal tissues obtained from The Cancer Genome Atlas (TCGA), and found 68 aberrantly expressed and prognosis-related ferroptosis-related lncRNAs. Based on this, we established an HCC prognostic model composed of 12 ferroptosis-related lncRNAs. In addition, HCC patients were divided into a high-risk group and a low-risk group according to the risk score of this 12 ferroptosis-related lncRNAs prognostic model. Gene enrichment analysis indicated that ferroptosis-related lncRNA-based expression signatures may regulate HCC immune microenvironment signaling pathways through ferroptosis, chemical carcinogenesis-reactive oxygen species, and NK cell-mediated cytotoxicity pathways. In addition, immune cell correlation analysis showed that there were significant differences in immune infiltrating cell subtypes, such as Th cells, macrophages, monocytes, and Treg cells between the two groups. In addition, the expression of multiple immune checkpoint molecules was found to be significantly increased in the high-risk group (eg, PD1, CTLA-4, CD86, etc.). Results: Our research provides a new method for predicting prognosis using a ferroptosis-related lncRNA expression signature prognostic model in hepatocellular carcinoma. And it provides new tools for predicting patient response and adverse effects of immunotherapy. Conclusion: In conclusion, ferroptosis-related lncRNA expression signatures can be used to construct a prognostic prediction model to predict the overall survival of HCC patients, and can be used as an independent influencing factor for prognosis. Further analysis showed that ferroptosis-related lncRNAs may affect the efficacy of immunotherapy in patients with HCC by altering the tumor microenvironment, so this model may serve as a new indicator of the response and irAEs of HCC to immunotherapy.

Discovery of a Novel, Potent, Orally Active, and Safe Inhibitor Targeting Human Mitochondrial RNA Polymerase.

High oxidative phosphorylation (OXPHOS) happens in some tumors, which depends on OXPHOS for energy supply, particularly in slow-cycling tumor cells. Therefore, targeting human mitochondrial RNA polymerase (POLRMT) to inhibit mitochondrial gene expression emerges as a potential therapeutic strategy to eradicate tumor cells. In this work, exploration and optimization of the first-in-class POLRMT inhibitor IMT1B and its SAR led to the identification of a novel compound D26, which exerted a strong antiproliferative effect on several cancer cells and decreased mitochondrial-related genes expression. In addition, mechanism studies demonstrated that D26 arrested cell cycle at the G1 phase and had no effect on apoptosis, depolarized mitochondria, or reactive oxidative stress generation in A2780 cells. Importantly, D26 exhibited more potent anticancer activity than the lead IMT1B in A2780 xenograft nude mice and had no observable toxic effect. All results suggest that D26 deserves to be further investigated as a potent and safe antitumor candidate.

Comparative Study of the Flavonoid Content in Radix Scutellaria from Different Cultivation Areas in China.

Scutellariabaicalensis Georgi, an important perennial herb, is widely distributed and used all over the world. The root of S. baicalensis (Radix Scutellaria) is rich in flavonoids with a variety of bioactive effects and is widely used in clinic. The different geographical and climatic conditions of different cultivated areas of S. baicalensis lead to the differences of the main components in Radix Scutellaria. The main objective of this study was to evaluate the difference of flavonoid content in Radix Scutellaria from different cultivated areas in China. The mobile phase system, elution gradient, detection wavelength, and other chromatographic conditions for high-performance liquid chromatography-diode array detection (HPLC-DAD) determination of 8 flavonoids in Radix Scutellaria were optimized. The contents of flavonoids in 38 samples of Radix Scutellaria collected from seven main genuine cultivated areas were determined, and the correlation between the content, cultivated area, and the biological activities of Radix Scutellaria was compared. The results implied that baicalin, wogonoside, and baicalein were the three main flavonoids with the highest contents in Radix Scutellaria. The content of flavonoids in different cultivated areas was very different, which had significant regionality and was closely related to the natural conditions of various places. The antioxidant and antitumor activities of the extract of Radix Scutellaria were closely related to the content of flavonoids, and high contents of baicalin, wogonoside, and baicalein positively improved biological activities.

Dedicated training of explosive strength in the abdominal core of soccer players / Treinamento dedicado da força explosiva no core abdominal dos jogadores de futebol / Entrenamiento específico de la fuerza explosiva en el core abdominal de futbolistas

ABSTRACT Introduction: Physical confrontation in soccer games presents greater demands on athletes' physical fitness. A soccer player's speed, strength, flexibility, coordination, endurance, and explosiveness can affect the body's fighting capacity. Objective: This study analyzes the relationship between strength training in soccer players' abdominal core and physical fitness. Methods: The effect of abdominal core stability strength training on performance improvement in volunteer soccer players selected as research subjects was verified by random division into two groups (experimental and control groups). Both groups performed daily training. The experimental group added special abdominal core training. Mathematical-statistical algorithms were used to statistically analyze the physical indicators of the two groups of volunteers. Results: The indices of physical fitness and body explosiveness of the two groups of athletes were significantly improved (P<0.05). After systematic training, the competition performance of the experimental group and the physiological and biochemical indicators were better than the control group (P<0.05). Conclusion: After abdominal core training, soccer players' physical fitness and explosive power indexes were improved. Research shows that strength training can help improve abdominal core performance in soccer players. It is recommended that coaches implement abdominal core strength training in the daily training of athletes. Level of evidence II; Therapeutic studies - investigation of treatment outcomes.

RESUMO Introdução: O confronto físico nos jogos de futebol apresenta maiores exigências quanto à aptidão física dos atletas. A velocidade, força, flexibilidade, coordenação, resistência e explosividade de um jogador de futebol podem afetar a capacidade de combate corporal. Objetivo: Este estudo visa analisar a relação entre o treinamento de força no core abdominal dos jogadores de futebol e sua aptidão física. Métodos: O efeito do treinamento de força da estabilidade do core abdominal sobre a melhoria do desempenho nos jogadores de futebol voluntários selecionados como objetos de pesquisa foi verificado por divisão aleatória em dois grupos (grupos experimentais e grupos de controle). Ambos os grupos realizavam treinamentos diários. O grupo experimental acrescentou treinamento especial de core abdominal. Foram utilizados algoritmos matemáticos-estatísticos para analisar os indicadores físicos dos dois grupos de voluntários de forma estatística. Resultados: Os índices de aptidão física e explosividade corporal dos dois grupos de atletas foram significativamente melhorados (P<0,05). Após o treinamento sistemático, o desempenho de competição do grupo experimental e os indicadores fisiológicos e bioquímicos foram melhores que os do grupo de controle (P<0,05). Conclusão: Após o treinamento do core abdominal, a aptidão física dos jogadores de futebol e os índices de potência explosiva foram melhorados. Pesquisas mostram que o treinamento da força pode ajudar a melhorar o desempenho do core abdominal nos jogadores de futebol. Recomenda-se aos treinadores a implementação do treino de força no core abdominal ao treinamento diário dos atletas. Nível de evidência II; Estudos terapêuticos - investigação dos resultados do tratamento.

RESUMEN Introducción: El enfrentamiento físico en los partidos de fútbol presenta mayores exigencias a la aptitud física de los atletas. La velocidad, la fuerza, la flexibilidad, la coordinación, la resistencia y la explosividad de un jugador de fútbol pueden afectar a la capacidad de combate del cuerpo. Objetivo: Este estudio tiene como objetivo analizar la relación entre el entrenamiento de la fuerza en el core de los jugadores de fútbol y su condición física. Métodos: El efecto del entrenamiento de la fuerza de la estabilidad del core abdominal sobre la mejora del rendimiento en jugadores de fútbol voluntarios seleccionados como sujetos de la investigación se verificó mediante la división aleatoria en dos grupos (grupo experimental y grupo de control). Ambos grupos realizaron un entrenamiento diario. El grupo experimental añadió un entrenamiento especial del core abdominal. Se utilizaron algoritmos matemático-estadísticos para analizar de forma estadística los indicadores físicos de los dos grupos de voluntarios. Resultados: Los índices de aptitud física y explosividad corporal de los dos grupos de atletas mejoraron significativamente (P<0,05). Tras el entrenamiento sistemático, el rendimiento en competición del grupo experimental y los indicadores fisiológicos y bioquímicos fueron mejores que los del grupo de control (P<0,05). Conclusión: Tras el entrenamiento del core abdominal, mejoraron la condición física y los índices de potencia explosiva de los futbolistas. Las investigaciones demuestran que el entrenamiento de fuerza puede ayudar a mejorar el rendimiento del core abdominal en los jugadores de fútbol. Se recomienda que los entrenadores implementen el entrenamiento de fuerza en el core abdominal al entrenamiento diario de los atletas. Nivel de evidencia II; Estudios terapéuticos - investigación de los resultados del tratamiento.

Impacts of suspension training on the physical fitness of swimmers / Impactos do treinamento de suspensão sobre a aptidão física de nadadores / Efectos del entrenamiento en suspensión en la aptitud física de los nadadores

ABSTRACT Introduction Suspension training develops the physical fitness of a swimmer and improves his or her abilities. The specific fitness of a swimmer is the body's ability to adapt to load in swimming. This is also a comprehensive reflection of their physical function, conditioning, athletic ability, and overall health. Objective This study aimed to analyze the effect of suspension training on swimmers' balance, abdominal center strength, and athletic performance. Methods This paper selects several swimmers as research volunteers. They were randomly divided into experimental and control groups. Both of them underwent physical training for three months. The experimental group adopted the suspension training method. The control group used traditional training methods. Mathematical statistics performed data analysis in both groups. Results The physical fitness of the two groups of swimmers was improved substantially after the experiment (P<0.05). The strength balance ability of the experimental group showed better performance(P<0.05). There was a significant difference between the experimental and control groups in the results of fitness index tests (P<0.01). Conclusion Suspension training has a prominent effect on the physical development of swimmers. This modality proved a better efficacy on swimmers' performance. Level of evidence II; Therapeutic studies - investigation of treatment outcomes.

RESUMO Introdução O treinamento em suspensão desenvolve a aptidão física de um nadador e aprimora suas habilidades. A aptidão física específica de um nadador é a capacidade corporal de adaptação à carga na natação. Isto é também um reflexo abrangente de sua função física, condicionamento, habilidade atlética e saúde geral. Objetivo Este estudo teve como objetivo analisar o efeito do treinamento em suspensão no equilíbrio da força do centro abdominal e no desempenho atlético dos nadadores. Métodos Este artigo seleciona vários nadadores como voluntários de pesquisa. Eles foram divididos aleatoriamente em grupo experimental e grupo de controle. Ambos foram submetidos a treinamento físico durante três meses. O grupo experimental adotou o método de treinamento em suspensão. O grupo de controle utilizou métodos de treinamento tradicionais. A análise dos dados nos dois grupos foi executada por estatísticas matemáticas. Resultados A aptidão física dos dois grupos de nadadores foi aprimorada substancialmente após o experimento (P<0,05). A capacidade de equilíbrio de força do grupo experimental demonstrou um melhor desempenho(P<0,05). Houve uma diferença significativa entre os grupos experimental e de controle nos resultados dos testes de índice de aptidão física (P<0,01). Conclusão O treinamento de suspensão tem um efeito destacado sobre o desenvolvimento físico dos nadadores. Esta modalidade comprovou uma melhor eficácia sobre o desempenho dos nadadores.Nível de evidência II; Estudos terapêuticos - investigação dos resultados do tratamento.

RESUMEN Introducción El entrenamiento en suspensión desarrolla la aptitud física de un nadador y mejora sus habilidades. La condición física específica de un nadador es la capacidad del cuerpo para adaptarse a la carga en la natación. También es un reflejo exhaustivo de su función física, su acondicionamiento, su capacidad atlética y su salud en general. Objetivo Este estudio tiene como objetivo analizar el efecto del entrenamiento en suspensión sobre el equilibrio de la fuerza del centro abdominal y el rendimiento deportivo de los nadadores. Métodos Este trabajo selecciona a varios nadadores como voluntarios para la investigación. Se dividieron aleatoriamente en grupo experimental y grupo de control. Ambos fueron sometidos a un entrenamiento físico durante tres meses. El grupo experimental adoptó el método de entrenamiento en suspensión. El grupo de control utilizó métodos de entrenamiento tradicionales. El análisis de los datos en ambos grupos se realizó mediante estadística matemática. Resultados La aptitud física de los dos grupos de nadadores mejoró sustancialmente después del experimento (P<0,05). La capacidad de equilibrio de la fuerza del grupo experimental mostró un mejor rendimiento (P<0,05). Hubo una diferencia significativa entre los grupos experimental y de control en los resultados de las pruebas del índice de aptitud física (P<0,01). Conclusión El entrenamiento en suspensión tiene un efecto destacado en el desarrollo físico de los nadadores. Esta modalidad demostró una mayor eficacia en el rendimiento de los nadadores. Nivel de evidencia II; Estudios terapéuticos - investigación de los resultados del tratamiento.

Design, Synthesis, and Biological Evaluation of Novel Chromanone Derivatives as Multifunctional Agents for the Treatment of Alzheimer's Disease.

Based on a multitarget strategy, a series of novel chromanone-1-benzyl-1,2,3,6-tetrahydropyridin hybrids were identified for the potential treatment of Alzheimer's disease (AD). Biological evaluation demonstrated that these hybrids exhibited significant inhibitory activities toward acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B). The optimal compound C10 possessed excellent dual AChE/MAO-B inhibition both in terms of potency and equilibrium (AChE: IC50 = 0.58 ± 0.05 µM; MAO-B: IC50 = 0.41 ± 0.04 µM). Further molecular modeling and kinetic investigations revealed that compound C10 was a dual-binding inhibitor bound to both the catalytic anionic site and peripheral anionic site of AChE. In addition, compound C10 exhibited low neurotoxicity and potently inhibited AChE enzymatic activity. Furthermore, compound C10 more effectively protected against mitochondrial dysfunction and oxidation than donepezil, strongly inhibited AChE-induced amyloid aggregation, and moderately reduced glutaraldehyde-induced phosphorylation of tau protein in SH-SY5Y cells. Moreover, compound C10 displayed largely enhanced improvements in cognitive behaviors and spatial memory in a scopolamine-induced AD mice model with better efficacy than donepezil. Overall, the multifunctional profiles of compound C10 suggest that it deserves further investigation as a promising lead for the prospective treatment of AD.

Combining of chemotherapy with targeted therapy for advanced biliary tract cancer: A systematic review and meta-analysis.

BACKGROUND: Targeted therapy (TT) has resulted in controversial efficacy as first-line treatment for biliary tract cancer (BTC). More efficacy comparisons are required to clarify the overall effects of chemotherapy (CT) combined with TT and CT alone on advanced BTC. AIM: To conduct a meta-analysis of the available evidence on the efficacy of CT combined with TT for advanced BTC. METHODS: The PubMed, EMBASE, ClinicalTrials, Scopus and Cochrane Library databases were systematically searched for relevant studies published from inception to August 2022. Only randomized clinical trials (RCTs) including comparisons between the combination of gemcitabine-based CT with TT and CT alone as first-line treatment for advanced BTC were eligible (PROSPERO-CRD42022313001). The odds ratios (ORs) for the objective response rate (ORR) and hazard ratios (HRs) for both progression-free survival (PFS) and overall survival (OS) were calculated and analyzed. Subgroup analyses based on different targeted agents, CT regimens and tumor locations were prespecified. RESULTS: Nine RCTs with a total of 1361 individuals were included and analyzed. The overall analysis showed a significant improvement in ORR in patients treated with CT + TT compared to those treated with CT alone (OR = 1.43, 95%CI: 1.11-1.86, P = 0.007) but no difference in PFS or OS. Similar trends were observed in the subgroup treated with agents targeting epidermal growth factor receptor (OR = 1.67, 95%CI: 1.17-2.37, P = 0.004) but not in the subgroups treated with agents targeting vascular endothelial growth factor receptor or mesenchymal-epithelial transition factor. Notably, patients who received a CT regimen of gemcitabine + oxaliplatin in the CT + TT arm had both a higher ORR (OR = 1.75, 95%CI: 1.20-2.56, P = 0.004) and longer PFS (HR = 0.83, 95%CI: 0.70-0.99, P = 0.03) than those in the CT-only arm. Moreover, patients with cholangiocarcinoma treated with CT + TT had significantly increased ORR and PFS (ORR, OR = 2.06, 95%CI: 1.27-3.35, PFS, HR = 0.79, 95%CI: 0.66-0.94). CONCLUSION: CT + TT is a potential first-line treatment for advanced BTC that leads to improved tumor control and survival outcomes, and highlighting the importance of CT regimens and tumor types in the application of TT.

The Relationship between Phase Angle, Nutrition Status, and Complications in Patients with Pancreatic Head Cancer.

Phase angle (PhA), a bioimpedance parameter, is used to assess the nutrition status and body composition of patients. Patients with pancreatic head cancer often present with body composition changes that relate to adverse outcomes. PhA may be useful to evaluate prognosis in these patients, but data are deficient. We aim to explore the effects of PhA on nutrition evaluation and short-term outcome prediction in these patients. This prospective study included 49 participants with pancreatic head cancer who underwent pancreaticoduodenectomy (PD). All participants' nutritional status and postoperative complications were assessed using nutrition assessment tools and the Clavien−Dindo classification method, respectively. Spearman correlation analyses were used to evaluate the association between PhA, nutrition status, and postoperative complications. ROC curves were generated to evaluate the ability of PhA to predict malnutrition and complications and to determine the cutoff value. The PhA values of the nutritional risk group and the malnourished group were significantly lower than those of the well-nourished group (p < 0.05). PhA positively correlated with patients' nutrition status. Nineteen patients had postoperative complications, and the PhA value of the complication group was significantly lower than that of the non-complication group (4.94 vs. 5.47, p = 0.013). ROC curves showed that the cutoff point of PhA to predict malnutrition was 5.45 (AUC: 0.744), and the cutoff point of PhA to predict postoperative complications was 5.35 (AUC: 0.717). Our study indicates that PhA was associated with nutrition status and could be considered a nutrition assessment tool for pancreatic head cancer patients and predict the postoperative complications of these patients who have undergone PD.

Characteristic Synthesis of a Covalent Organic Framework and Its Application in Multifunctional Tumor Therapy.

For decades, covalent organic frameworks (COFs) have attracted wide biomedical interest due to their unique properties including ease of synthesis, porosity, and adjustable biocompatibility. Versatile COFs can easily encapsulate various therapeutic drugs due to their extremely high payload and porosity. COFs with abundant functional groups can be surface-modified to achieve active targeting and enhance biocompatibility. In this paper, the latest developments of COFs in the biomedical field are summarized. First, the classification and synthesis of COFs are discussed. Cancer diagnosis and treatment based on COFs are studied, and the advantages and limitations of each method are discussed. Second, the specific preparation methods to obtain specific therapeutic properties are summarized. Finally, based on the combination and modification of COFs with various components, this review system summarizes different combination therapies. In addition, the main challenges faced in COF research and prospects for applying COFs to cancer diagnosis and treatment are evaluated. This review provides enlightening insights into the interdisciplinary research on COFs and applications in biomedicine, which highlight the great expectations for their further clinical transformation.

Metabolomic Profiling Identified Serum Metabolite Biomarkers and Related Metabolic Pathways of Colorectal Cancer.

BACKGROUND: The screening and early detection of colorectal cancer (CRC) still remain a challenge due to the lack of reliable and effective serum biomarkers. Thus, this study is aimed at identifying serum biomarkers of CRC that could be used to distinguish CRC from healthy controls. METHODS: A prospective 1 : 2 individual matching case-control study was performed which included 50 healthy control subjects and 98 CRC patients. Untargeted metabolomic profiling was conducted with liquid chromatography tandem mass spectrometry (LC-MS/MS) to identify CRC-related metabolites and metabolic pathways. RESULTS: In total, 178 metabolites were detected, and an orthogonal partial least-squares-discriminant analysis (OPLS-DA) model was useful to distinguish CRC patients from healthy controls. Nine metabolites showed significantly differential serum levels in CRC patients under the conditions of variable importance in projection (VIP) > 1, p < 0.05 using Student's t-test, and fold change (FC) ≥ 1.2 or ≤0.5. The above nine metabolites were 3-hydroxybutyric acid, hexadecanedioic acid, succinic acid semialdehyde, 4-dodecylbenzenesulfonic acid, prostaglandin B2, 2-pyrocatechuic acid, xanthoxylin, 12-hydroxydodecanoic acid, and formylanthranilic acid. Four potential biomarkers were identified to diagnose CRC through ROC curves: hexadecanedioic acid, 4-dodecylbenzenesulfonic acid, 2-pyrocatechuic acid, and formylanthranilic acid. All AUC values of these four serum biomarkers were above 0.70. In addition, the exploratory analysis of metabolic pathways revealed the activated states for the vitamin B metabolic pathway and the alanine, aspartate, and glutamate metabolic pathways associated with CRC. CONCLUSION: The 4 identified potential metabolic biomarkers could discriminate CRC patients from healthy controls, and the 2 metabolic pathways may be activated in the CRC tissues.

Biliary Neuroendocrine Neoplasms: Analysis of Prognostic Factors and Development and Validation of a Nomogram.

BACKGROUND: For this study, we explored the prognostic profiles of biliary neuroendocrine neoplasms (NENs) patients and identified factors related to prognosis. Further, we developed and validated an effective nomogram to predict the overall survival (OS) of individual patients with biliary NENs. METHODS: We included a total of 446 biliary NENs patients from the SEER database. We used Kaplan-Meier curves to determine survival time. We employed univariate and multivariate Cox analyses to estimate hazard ratios to identify prognostic factors. We constructed a predictive nomogram based on the results of the multivariate analyses. In addition, we included 28 biliary NENs cases from our center as an external validation cohort. RESULTS: The median survival time of biliary NENs from the SEER database was 31 months, and the value of gallbladder NENs (23 months) was significantly shorter than that of the bile duct (45 months) and ampulla of Vater (33.5 months, p=0.023). Multivariate Cox analyses indicated that age, tumor size, pathological classification, SEER stage, and surgery were independent variables associated with survival. The constructed prognostic nomogram demonstrated good calibration and discrimination C-index values of 0.783 and 0.795 in the training and validation dataset, respectively. CONCLUSION: Age, tumor size, pathological classification, SEER stage, and surgery were predictors for the survival of biliary NENs. We developed a nomogram that could determine the 3-year and 5-year OS rates. Through validation of our central database, the novel nomogram is a useful tool for clinicians in estimating individual survival among biliary NENs patients.

Biliary diversion increases resting energy expenditure leading to decreased blood glucose level in mice with type 2 diabetes.

AIMS/INTRODUCTION: Type 2 diabetes mellitus is a group of metabolism abnormalities in carbohydrates and energy. Our aim was to investigate resting energy expenditure (REE) and blood glucose changes after biliary diversion in mice with diabetes. MATERIALS AND METHODS: Male mice with diabetes were randomly divided into biliary diversion and sham groups. REE was detected by indirect calorimetry, the levels of fasting blood glucose, total bile acids and triiodothyronine were analyzed. After mice were killed, the weight amount of brown adipose tissue (BAT) and gastrocnemius was measured, and the expression level of G protein-coupled bile acid receptor and type 2 iodothyronine deiodinase in BAT and gastrocnemius were examined. RESULTS: The two groups of mice were pair-fed, the bodyweights (P < 0.001) and the fasting blood glucose level (P < 0.001) in the biliary diversion group significantly decreased 24 weeks after surgery. The intraperitoneal glucose tolerance test (P = 0.035) and oral glucose tolerance test (P = 0.027) showed improvement in glucose tolerance after surgery. The REE level significantly increased 24 weeks after surgery (P = 0.005), the levels of total bile acids (P = 0.014) and triiodothyronine (P < 0.001) increased at the 24th postoperative week. The weight ratio of BAT (P = 0.038) and gastrocnemius (P = 0.026) in the biliary diversion group were higher than that in the sham group. The expression of G protein-coupled bile acid receptor in BAT (P < 0.001) and gastrocnemius (P = 0.003) were upregulated after surgery, and the type 2 iodothyronine deiodinase expression also increased in BAT (P = 0.015) and gastrocnemius (P = 0.015). CONCLUSIONS: The REE level increased and the glucose metabolism improved in mice with diabetes after biliary diversion.

The Prognostic Impact of Pathology on Patients With Pseudomyxoma Peritonei Undergoing Debulking Surgery: A Systematic Review and Meta-Analysis of Retrospective Studies.

Background: Pseudomyxoma peritonei (PMP) is a rare clinical condition with fatal outcomes, which is characterized by the progressive accumulation of mucinous ascites and peritoneal implants. Some studies have reported the effect of PMP biology on patient outcome. The objective of this study was to analyze published articles focusing on the impact of pathology on the prognosis of PMP patients undergoing debulking. Methods: Data from all studies regarding the prognosis of patients, with different pathologies, who underwent debulking surgery were analyzed. We searched PubMed, the Wiley Online Library, Ovid, and the Cochrane Library (through January 2020). Studies were confined to those articles written in English. Five studies were identified, and the differences in 5-year survival rates were analyzed according to the Kaplan-Meier survival curves. The hazard ratios (HRs) of the 5-year survival rates were calculated. Results: The mean and median 5-year survival rates of all patients were 39 and 40%, respectively. The median overall survival was 49.3 months. The mean 5-year survival rates of low-grade PMP was 45.2%. The five studies had sufficient data to calculate HRs from the 5-year survival rates data, and three had HRs lower than 1. The total HRs was 0.54, with a 95% CI between 0.33 and 0.89 (P = 0.01). Conclusions: Among PMP patients receiving debulking surgery who are not able to undergo complete cytoreductive surgery, low-grade biological PMP had a better prognosis than high-grade PMP.

[Effect of Regulating A20 Expression on NF-κB Expression and Biological Characteristics of Jurkat Cells].

OBJECTIVE: To explore the effect of regulating A20 expression on NF-κB and biological characteristics of Jurkat cells with glucocorticoid (GC) resistance. METHODS: CCRF CEM and Jurkat cells were treated with dexamethasone (DEX) at concentrations of 100、10、1、0.1、0.01 and 0.001 µmol/L, and cultured for 24、48 and 72 h. The proliferation inhibition rate of Jurkat cell was detected by CCK-8. A20 plasmid was constructed, A20-siRNA was designed and synthesized, and transfected into Jurkat cells by liposome. CCK-8 was used to detect the proliferation rates of Jurkat cells in different concentrations of DEX group, DEX combined with A20 plasmid group and A20-siRNA group. The mRNA expression level of NF-κB was detected by RT-qPCR, the protein expression level of NF-κB was detected by Western blot, and the apoptosis of Jurkat cells was examined by flow cytometry. RESULTS: The inhibitory effects of DEX at different concentrations on the growth of CCRF CEM cells were time-dependent (r=0.984, P＜0.05) and concentration-dependent (r=0.966, P＜0.05). At the point of 24 hour, the IC50 approached 1 µmol/L in CCRF CEM cells. Great large differences began to appear between 1 and 10 µmol/L, the proliferation rate of Jurkat cells treated with 1 µmol/L DEX did not show a significant change. Therefore, 1 µmol/L was selected as control group. The cell proliferation rate of A20 plasmid transfection combined with different concentrations of DEX group was lower than that of DEX group and A20-siRNA combined with DEX group. After transfection of A20 plasmid, the expression level of NF-κB was significantly lower than that of control group (P＜0.05), and the apoptotic rate was significantly higher than that of control group (P＜0.05). After transfection of Jurkat cells with A20-siRNA, the expression level of NF-κB was significantly higher than that of control group (P＜0.05). The apoptotic rate of cells in A20-siRNA group was not significantly changed (P＞0.05). CONCLUSION: Jurkat cells are resistant to DEX. A20 overexpression combined with DEX can increase sensitivity of Jurkat cells with GC resistance and decrease the proliferation rate of Jurkat cells, down-regulate the expression level of NF-κB and promote the apoptosis of Jurkat cells.