Nomogram based on liver stiffness and spleen area with ultrasound for posthepatectomy liver failure: A multicenter study.

BACKGROUND: Liver stiffness (LS) measurement with two-dimensional shear wave elastography (2D-SWE) correlates with the degree of liver fibrosis and thus indirectly reflects liver function reserve. The size of the spleen increases due to tissue proliferation, fibrosis, and portal vein congestion, which can indirectly reflect the situation of liver fibrosis/cirrhosis. It was reported that the size of the spleen was related to posthepatectomy liver failure (PHLF). So far, there has been no study combining 2D-SWE measurements of LS with spleen size to predict PHLF. This prospective study aimed to investigate the utility of 2D-SWE assessing LS and spleen area (SPA) for the prediction of PHLF in hepatocellular carcinoma (HCC) patients and to develop a risk prediction model. AIM: To investigate the utility of 2D-SWE assessing LS and SPA for the prediction of PHLF in HCC patients and to develop a risk prediction model. METHODS: This was a multicenter observational study prospectively analyzing patients who underwent hepatectomy from October 2020 to March 2022. Within 1 wk before partial hepatectomy, ultrasound examination was performed to measure LS and SPA, and blood was drawn to evaluate the patient's liver function and other conditions. Least absolute shrinkage and selection operator logistic regression and multivariate logistic regression analysis was applied to identify independent predictors of PHLF and develop a nomogram. Nomogram performance was validated further. The diagnostic performance of the nomogram was evaluated with receiver operating characteristic curve compared with the conventional models, including the model for end-stage liver disease (MELD) score and the albumin-bilirubin (ALBI) score. RESULTS: A total of 562 HCC patients undergoing hepatectomy (500 in the training cohort and 62 in the validation cohort) were enrolled in this study. The independent predictors of PHLF were LS, SPA, range of resection, blood loss, international normalized ratio, and total bilirubin. Better diagnostic performance of the nomogram was obtained in the training [area under receiver operating characteristic curve (AUC): 0.833; 95% confidence interval (95%CI): 0.792-0.873; sensitivity: 83.1%; specificity: 73.5%] and validation (AUC: 0.802; 95%CI: 0.684-0.920; sensitivity: 95.5%; specificity: 52.5%) cohorts compared with the MELD score and the ALBI score. CONCLUSION: This PHLF nomogram, mainly based on LS by 2D-SWE and SPA, was useful in predicting PHLF in HCC patients and presented better than MELD score and ALBI score.

Reproducibility study of intravoxel incoherent motion and apparent diffusion coefficient parameters in normal pancreas.

BACKGROUND: The consistency of pancreatic apparent diffusion coefficient (ADC) values and intravoxel incoherent motion (IVIM) parameter values across different magnetic resonance imaging (MRI) devices significantly impacts the patient's diagnosis and treatment. AIM: To explore consistency in image quality, ADC values, and IVIM parameter values among different MRI devices in pancreatic examinations. METHODS: This retrospective study was approved by the local ethics committee, and informed consent was obtained from all participants. In total, 22 healthy volunteers (10 males and 12 females) aged 24-61 years (mean, 28.9 ± 2.3 years) underwent pancreatic diffusion-weighted imaging using 3.0T MRI equipment from three vendors. Two independent observers subjectively scored image quality and measured the pancreas's overall ADC values and signal-to-noise ratios (SNRs). Subsequently, regions of interest (ROIs) were delineated for the IVIM parameters (true diffusion coefficient, pseudo-diffusion coefficient, and perfusion fraction) using post-processing software. These ROIs were on the head, body, and tail of the pancrease. The subjective image ratings were assessed using the kappa consistency test. Intraclass correlation coefficients (ICCs) and mixed linear models were used to evaluate each device's quantitative parameter values. Finally, a pairwise analysis of IVIM parameter values across each device was performed using Bland-Altman plots. RESULTS: The Kappa value for the subjective ratings of the different observers was 0.776 (P < 0.05). The ICC values for inter-observer and intra-observer agreements for the quantitative parameters were 0.803 [95% confidence interval (CI): 0.684-0.880] and 0.883 (95%CI: 0.760-0.945), respectively (P < 0.05). The ICCs for the SNR between different devices was comparable (P > 0.05), and the ICCs for the ADC values from different devices were 0.870, 0.707, and 0.808, respectively (P < 0.05). Notably, only a few statistically significant inter-device agreements were observed for different IVIM parameters, and among those, the ICC values were generally low. The mixed linear model results indicated differences (P < 0.05) in the f-value for the pancreas head, D-value for the pancreas body, and D-value for the pancreas tail obtained using different MRI machines. The Bland-Altman plots showed significant variability at some data points. CONCLUSION: ADC values are consistent among different devices, but the IVIM parameters' repeatability is moderate. Therefore, the variability in the IVIM parameter values may be associated with using different MRI machines. Thus, caution should be exercised when using IVIM parameter values to assess the pancreas.

Corrigendum: Characterizing the neutrophilic inflammation in chronic rhinosinusitis with nasal polyps.

[This corrects the article DOI: 10.3389/fcell.2021.793073.].

Discovery of Novel Imidazo[1,2-a]pyridine-Based HDAC6 Inhibitors as an Anticarcinogen with a Cardioprotective Effect.

Cardiotoxicity associated with chemotherapy has gradually become the major cause of death in cancer patients. The development of bifunctional drugs with both cardioprotective and antitumor effects has become the future direction. HDAC6 plays important roles in the progression, treatment, and prognosis of cancer and cardiovascular diseases, but bifunctional inhibitors have not been reported. Herein, structure-activity relationship studies driven by pharmacophore-based remodification and fragment-based design were performed to yield highly potent HDAC6 inhibitor I-c4 containing imidazo[1,2-a]pyridine. Importantly, I-c4 effectively suppressed the growth of MGC-803 xenografts in vitro and in vivo by inhibiting the deacetylation pathway without causing myocardial damage after long-term administration. Meanwhile, I-c4 could mitigate severe myocardial damage against H2O2 or myocardial ischemia/reperfusion in vitro and in vivo. Further studies revealed that the cardioprotective effect of I-c4 was associated with reduction of inflammatory cytokines. Taken together, I-c4 may represent a novel lead compound for further development of an anticarcinogen with a cardioprotective effect.

Structure and Function of Somatostatin and its Receptors in Endocrinology.

Somatostatin analogs, such as octreotide (OCT), lanreotide, and pasireotide, which function as somatostatin receptor ligands (SRLs), are the main drugs used for the treatment of acromegaly. These ligands are also used as important molecules for radiation therapy and imaging of neuroendocrine tumors (NETs). Somatostatin receptors (SSTRs) are canonical G protein-coupled proteins (GPCRs) that play a role in metabolism, growth, and pathological conditions such as hormone disorders, neurological diseases, and cancers. Cryogenic electron microscopy (cryo-EM) combined with the protein structure prediction platform AlphaFold has been used to determine the three-dimensional structures of many proteins. Recently, several groups published a series of papers illustrating the three-dimensional structure of SSTR2, including that of the inactive/activated SSTR2-G protein complex bound to different ligands. The results revealed the residues that contribute to the ligand binding pocket and demonstrated that Trp8-Lys9 (the W-K motif) in somatostatin analogs is the key motif in stabilizing the bottom part of the binding pocket. In this review, we discuss the recent findings related to the structural analysis of SSTRs and SRLs, the relationships between the structural data and clinical findings, and the future development of novel structure-based therapies.

The Role of Serine Protease 8 in Mediating Gefitinib Resistance in Non-small Cell Lung Cancer.

OBJECTIVE: This investigation aims to explore the expression levels of serine protease 8 (PRSS8) in gefitinib-resistant Non-Small Cell Lung Cancer (NSCLC) cell lines (PC9/GR) and elucidate its mechanism of action. METHODOLOGY: We measured PRSS8 expression in gefitinib-resistant (PC9/GR) and sensitive (PC9) NSCLC cell lines using Western blot analysis. PRSS8-specific small interfering RNA (PRSS8-siRNA), a recombinant plasmid, and a corresponding blank control were transfected into PC9/GR cells. Subsequently, Western blot analyses were conducted to assess the expression levels of PRSS8, phosphorylated AKT (p-AKT), AKT, phosphorylated mTOR (p-mTOR), mTOR, and various apoptosis-related proteins within each group. Additionally, a cell proliferation assay utilizing Cell Counting Kit-8 (CCK8) was performed on each group treated with gefitinib. RESULT: PRSS8 expression was markedly higher in PC9/GR cells compared to PC9 cells (p < 0.05). The group treated with PRSS8-siRNA exhibited significantly reduced protein expression levels of PRSS8, p-AKT, p-mTOR, ß-catenin, and BCL-2 compared to the control siRNA (Con-siRNA) group, whereas expressions of Caspase9 and Bax were significantly increased. In the untransfected PC9/GR cells, protein expressions of PRSS8, p-AKT, pmTOR, and BCL-2 were significantly elevated when compared with the plasmid-transfected group, which also showed a significant reduction in Bax expression. The proliferative activity of the PRSS8-siRNA group postgefitinib treatment was significantly diminished at 24, 48, and 72 hours in comparison to the Con-siRNA group. CONCLUSION: The findings indicate that PRSS8 contributes to the acquisition of resistance to gefitinib in NSCLC, potentially through regulation of the AKT/mTOR signaling pathway.

Evaluation of the FPMC respiratory panel for detection of respiratory tract pathogens in nasopharyngeal swab and sputum specimens.

OBJECTIVES: The performance of the new Respiratory Pathogen panel (fluorescent probe melting curve, FPMC) for the qualitative detection of 12 organisms (chlamydia pneumoniae, mycoplasma pneumoniae, adenovirus, influenza A virus, influenza B virus, parainfluenza virus, rhinovirus, etc.) was assessed. METHODS: Prospectively collected nasopharyngeal swab (NPS) and sputum specimens (n = 635) were detected by using the FPMC panel, with the Sanger sequencing method as the comparative method. RESULTS: The overall percent concordance between the FPMC analysis method and the Sanger sequencing method was 100% and 99.66% for NPS and sputum specimens, respectively. The FPMC testified an overall positive percent concordance of 100% for both NPS and sputum specimens. The FPMC analysis method also testified an overall negative percent concordance of 100% and 99.38% for NPS and sputum specimens, respectively. CONCLUSIONS: The FPMC analysis method is a stable and accurate assay for rapid, comprehensive detecting for respiratory pathogens.

Targeting HTR2B suppresses non-functioning pituitary adenoma growth and sensitizes cabergoline treatment via inhibiting Gαq/PLC/PKCγ/STAT3 axis.

BACKGROUND: Managing non-functioning pituitary adenomas (NFPAs) is difficult due to limited drug treatments. Cabergoline's (CAB) effectiveness for NFPAs is debated. This study explores the role of HTR2B in NFPAs and its therapeutic potential. METHODS: We conducted screening of bulk RNA-sequencing data to analyze HTR2B expression levels in NFPA samples. In vitro and in vivo experiments were performed to evaluate the effects of HTR2B modulation on tumor growth and cell cycle regulation. Mechanistic insights into the HTR2B-mediated signaling pathway were elucidated using pharmacological inhibitors and molecular interaction assays. RESULTS: Elevated HTR2B expression was detected in NFPA samples, which was associated with increased tumor survival. Inhibition of HTR2B activity resulted in the suppression of tumor growth through modulation of the G2M cell cycle. The inhibition of HTR2B with PRX-08066 was found to block STAT3 phosphorylation and nuclear translocation by interfering with the Gαq/PLC/PKC pathway. A direct interaction between PKC-γ and STAT3 was critical for STAT3 activation. CAB was shown to activate pSTAT3 via HTR2B, reducing its therapeutic potential. However, the combination of an HTR2B antagonist with CAB significantly inhibited tumor cell proliferation in HTR2B-expressing pituitary tumor cell lines, a xenografted pituitary tumor model, and patient-derived samples. Analysis of patient-derived data indicated that a distinct molecular pattern characterized by upregulated HTR2B/PKC-γ and downregulated BTG2/GADD45A may benefit from combination treatment with CAB and PRX-08066. CONCLUSIONS: HTR2B is a potential therapeutic target for NFPAs, and its inhibition could improve CAB efficacy. A dual therapy approach may be beneficial for NFPA patients with high HTR2B expression.

γ-Tocotrienol enhances autophagy of gastric cancer cells by the regulation of GSK3ß/ß-Catenin pathway.

γ-Tocotrienol (γ-T3) is a major subtype of vitamin E, mainly extracted from palm trees, barley, walnuts, and other plants. γ-T3 has effects on anti-inflammation, anti-oxidation, and potential chemoprevention against malignancies. It is still uncompleted to understand the effect of γ-T3 on the inhibitory mechanism of cancer. This study aimed to investigate whether γ-T3 enhanced autophagy in gastric cancer and the underlying molecular mechanism. The results showed that γ-T3 (0-90 µmol/L) inhibited the proliferation of gastric cancer MKN45 cells and AGS cells, and arrested the cell cycle at the G0/G1 phase in a dose-dependent manner. Autophagy was increased in MKN45 cells treated with γ-T3 (0-45 µmol/L), especially at a dose of 30 µmol/L for 24 h. These effects were reversed by 3-methyladenine pretreatment. Furthermore, γ-T3 (30 µmol/L) also significantly downregulated the expression of pGSK-3ß (ser9) and ß-catenin protein in MKN45 cells, and γ-T3 (20 mg/kg b.w.) effectively decreased the growth of MKN45 cell xenografts in BABL/c mice. GSK-3ß inhibitor-CHIR-99021 reversed the negative regulation of GSK-3ß/ß-Catenin signaling and autophagy. Our findings indicated that γ-T3 enhances autophagy in gastric cancer cells mediated by GSK-3ß/ß-Catenin signaling, which provides new insights into the role of γ-T3 enhancing autophagy in gastric cancer.

VALD-2 mitigates cisplatin-induced acute kidney injury: Mechanistic insights into oxidative stress modulation and inflammation suppression.

This study explores the compelling antitumor properties of VALD-2, a synthetic Schiff base ligand known for its low toxicity. The focus is on investigating VALD-2's protective role against cisplatin-induced acute kidney injury (AKI) in mice, with a specific emphasis on mitigating oxidative stress and inflammation. The study involves daily intraperitoneal injections of amifostine or VALD-2 over 7 days to establish an AKI model. Subsequently, mice were assigned to normal control, cisplatin group, cisplatin + amifostine group, and cisplatin + VALD-2 10 mg/kg group, cisplatin + VALD-2 20 mg/kg, and cisplatin + VALD-2 40 mg/kg. Kidney injury is assessed through serum blood urea nitrogen (BUN) and creatinine (Cr) activity assays. Levels of inflammatory factors, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), in kidney tissue of mice were assessed through enzyme-linked immunosorbent assay (ELISA). The protective effect of VALD-2 is further examined through HE staining to observe pathological changes in kidney injury. The ultrastructural changes of renal cells and tubular epithelial cells were observed by electron microscopy under experimental conditions, indicating the effect of VALD-2 on reversing cisplatin-induced renal injury. The study delves into VALD-2's protective mechanisms against cisplatin-induced kidney injury by using western blot analysis to assess the expression levels of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and malondialdehyde (MDA) in kidney tissues. VALD-2 demonstrates significant improvement in cisplatin-induced AKI, as evidenced by increased BUN and Cr levels. It effectively protects kidney tissue from oxidative damage, enhancing SOD and GSH-Px activities while reducing MDA levels. The study also reveals a decrease in TNF-α and IL-6 levels, supported by ELISA results, and histological findings confirm anti-nephrotoxic effects. Western blot analysis shows an upregulation of antioxidant enzymes (SOD, GSH-Px) and a reduction in MDA production. VALD-2 emerges as a promising mitigator of cisplatin-induced AKI, showcasing its ability to enhance oxidative stress-related protein expression. The findings suggest VALD-2 as a potential therapeutic agent for protecting against cisplatin-induced kidney injury.

Physicochemical stability of corn protein hydrolysate/tannic acid complex-based ß-carotene nanoemulsion delivery system.

Moderate non-covalent interaction of protein and polyphenols can improve the emulsifying property of protein itself. The corn protein hydrolysate (CPH) and tannic acid (TA) complex was successfully used to construct nanoemulsion for algal oil delivery. There has been no study on the feasibility of this nanoemulsion delivery system for other food functional components, for example, ß-carotene (ß-CE). CPH/TA complex-based nanoemulsion system for ß-CE delivery was studied, focusing on the effect of ß-CE content on the physicochemical stability of the nanoemulsions. The nanoemulsion delivery systems (dia. 150 nm) with low viscosity and good liquidity were easily fabricated by two-step emulsification. The nanoemulsions with high ß-CE content (>71.5 µg/mL) significantly increased (p < .05) the emulsion droplet size. However, there was no significant (p > .05) effect of ß-CE content on polydispersity index (PDI) and zeta potential of the nanoemulsions. The storage (30 days) experiment results demonstrated that the droplet size of the nanoemulsions with varying ß-CE content increased slightly during storage. However, the PDI values showed a slightly decreasing trend. Zeta potentials of the nanoemulsions showed no noticeable change during storage. Moreover, after storage of 30 days, the retention ratios of ß-CE were found to be up to 90%, which suggests an excellent protective effect for ß-CE by the nanoemulsion systems. The CPH/TA complex stabilized nanoemulsions could aggregate in gastric condition, but the ß-CE content did not have obvious effect on the digestive stability of the nanoemulsions. The CPH/TA complex could be employed as an emulsifier to construct a physicochemical stable nanoemulsion delivery system for lipophilic active components.

Exploring the therapeutic mechanism of curcumin in prostate cancer using network pharmacology and molecular docking.

Objective: Curcumin, a phenolic compound extracted from turmeric rhizomes, exhibits antitumour effects in preclinical models of tumours. However, its mechanism of action in prostate cancer remains unclear. Exploring the molecular mechanisms of curcumin in prostate cancer based on network pharmacology and molecular docking provides a new theoretical basis for prostate cancer treatment. Method: Using tools such as PharmMapper, SuperPred, TargetNet, and SwissTargetPrediction, we obtained information on curcumin-related targets. We comprehensively collected prostate cancer-related targets from several databases, including GeneCards, CTD, DisGeNET, OMIM, and PharmGKB. Cross-cutting drug-disease targets were then derived by screening using the Venny 2.1.0 tool. Subsequently, we used the DAVID platform to perform in-depth GO and KEGG enrichment analyses of the drug-disease-shared targets. To construct a PPI network map of the cross-targets and screen the 10 core targets, we combined the STRING database and Cytoscape 3.7.2. Molecular docking experiments were performed using AutoDockTools 1.5.7 software. Finally, we used several databases such as GEPIA, HPA, cBioPortal, and TIMER to further analyse the screened core targets in detail. Result: We identified 307 key targets of curcumin in cancer treatment. After GO functional enrichment analysis, we obtained 1119 relevant entries, including 782 biological progression (BP) entries, 112 cellular component (CC) entries, and 225 molecular function (MF) entries. In addition, KEGG pathway enrichment analysis revealed 126 signalling pathways, which were mainly involved in the cancer pathway, such as lipid and atherosclerosis pathway, PI3K-Akt signal pathway, MAPK signal pathway, Ras signal pathways, and chemical carcinogenesis-reactive oxygen species. By applying Cytoscape 3.7.2 software, we identified SRC, PIK3R1, STAT3, AKT1, HSP90AA1, ESR1, EGFR, HSP90AB1, MAPK8, and MAPK1 as core targets. Molecular docking experiments showed that the binding energies of curcumin to these core targets were all below -1.85 kJ mol-1, which fully demonstrated that curcumin could spontaneously bind to these core targets. Finally, these results were validated at multiple levels, including mRNA expression, protein expression, and immune infiltration. Conclusion: Through in-depth network pharmacology and molecular docking studies, we have found that curcumin may have anticancer potential by upregulating the expression of PIK3R1 and STAT3, and downregulating the binding ability of molecules such as SRC, AKT1, HSP90AA1, ESR1, EGFR, HSP90AB1, MAPK8, and MAPK1. In addition, curcumin may interfere with the cyclic process of prostate cancer cells by inhibiting key signalling pathways such as the PI3K-Akt signalling pathway, MAPK signalling pathway, and Ras, thereby inhibiting their growth. This study not only reveals the potential molecular mechanism of curcumin in the treatment of prostate cancer but also provides an important theoretical basis for subsequent research.

Attention-guided context asymmetric fusion networks for the liver tumor segmentation of computed tomography images.

Background: Liver tumor segmentation based on medical imaging is playing an increasingly important role in liver tumor research and individualized therapeutic decision-making. However, it remains a challenging in terms of the accuracy of automatic segmentation of liver tumors. Therefore, we aimed to develop a novel deep neural network for improving the results from the automatic segmentation of liver tumors. Methods: This paper proposes the attention-guided context asymmetric fusion network (AGCAF-Net), combining attention guidance and fusion context modules on the basis of a residual neural network for the automatic segmentation of liver tumors. According to the attention-guided context block (AGCB), the feature map is first divided into multiple small blocks, the local correlation between features is calculated, and then the global nonlocal fusion module (GNFM) is used to obtain the global information between pixels. Additionally, the context pyramid module (CPM) and asymmetric semantic fusion module (AFM) are used to obtain multiscale features and resolve the feature mismatch during feature fusion, respectively. Finally, we used the liver tumor segmentation benchmark (LiTS) dataset to verify the efficiency of our designed network. Results: Our results showed that AGCAF-Net with AFM and CPM is effective in improving the accuracy of liver tumor segmentation, with the Dice coefficient increasing from 82.5% to 84.1%. The segmentation results of liver tumors by AGCAF-Net were superior to those of several state-of-the-art U-net methods, with a Dice coefficient of 84.1%, a sensitivity of 91.7%, and an average symmetric surface distance of 3.52. Conclusions: AGCAF-Net can obtain better matched and accurate segmentation in liver tumor segmentation, thus effectively improving the accuracy of liver tumor segmentation.

Comprehensive pan-cancer investigation of carnosine dipeptidase 1 and its prospective prognostic significance in hepatocellular carcinoma.

Carnosine dipeptidase 1 (CNDP1), an enzyme integral to the hydrolysis of dipeptides containing histidine, plays an indispensable role in myriad physiological processes, including hydrolysis of proteins, maturation of specific biochemical functionalities within proteins, tissue regeneration, and regulation of cell cycle. However, the implications of CNDP1 in oncogenesis and its prognostic value are not yet fully elucidated. Initially, we procured the GSE40367 dataset from the Gene Expression Omnibus and established a protein-protein interaction network. Thereafter, we conducted functional and pathway enrichment analyses utilizing GO, KEGG, and GSEA. Moreover, we undertook an association analysis concerning the expression of CNDP1 with immune infiltration, along with survival analysis across various cancers and specifically in hepatocellular carcinoma (HCC). Our study uncovered a total of 2,248 differentially expressed genes, with a down-regulation of CNDP1 in HCC and other cancers. Our explorations into the relationship between CNDP1 and immune infiltration disclosed a negative correlation between CNDP1 expression and the presence of immune cells in HCC. Survival analyses revealed that diminished expression of CNDP1 correlates with an adverse prognosis in HCC and several other types of cancer. These observations intimate that CNDP1 holds promise as a novel prognostic biomarker for both pan-cancer and HCC.

Nutritional risk factors in patients with nasopharyngeal carcinoma: a cross-sectional study.

Background: Patients with nasopharyngeal carcinoma are notably susceptible to high nutritional risks. If not addressed, this susceptibility can lead to malnutrition, resulting in numerous adverse clinical outcomes. Despite the significance of this issue, there is limited comprehensive research on the topic. Objective: The objective of our study was to identify nutritional risk factors in patients with nasopharyngeal carcinoma. Methods: For this cross-sectional study, we recruited a total of 377 patients with nasopharyngeal carcinoma. The Nutritional Risk Screening 2002 tool was used to assess their nutritional risk. These patients were divided into a well-nourished group (n = 222) and a nutritional risk group (n = 155). Potential risk factors were screened out using univariate analysis (p < 0.1). These factors were subsequently analyzed with multivariate logistic regression analysis (p < 0.05) to identify the nutritional risk factors for these patients. Results: Our findings indicated that increasing age (OR = 1.085, 95%CI: 1.053-1.117, p < 0.001), high number of radiation treatments (OR = 1.103, 95%CI: 1.074-1.132, p < 0.001), low BMI (OR = 0.700, 95%CI: 0.618-0.793, p < 0.001), and low albumin levels (OR = 0.852, 95%CI: 0.789-0.921, p < 0.001) are significant nutritional risk factors in patients with nasopharyngeal carcinoma. Conclusion: Increasing age, high number of radiation treatments, low BMI, and low albumin levels are significant nutritional risk factors in patients with nasopharyngeal carcinoma.

Oncoprotein LAMTOR5-mediated CHOP silence via DNA hypermethylation and miR-182/miR-769 in promotion of liver cancer growth.

C/EBP homologous protein (CHOP) triggers the death of multiple cancers via endoplasmic reticulum (ER) stress. However, the function and regulatory mechanism of CHOP in liver cancer remain elusive. We have reported that late endosomal/lysosomal adapter, mitogen-activated protein kinase and mTOR activator 5 (LAMTOR5) suppresses apoptosis in various cancers. Here, we show that the transcriptional and posttranscriptional inactivation of CHOP mediated by LAMTOR5 accelerates liver cancer growth. Clinical bioinformatic analysis revealed that the expression of CHOP was low in liver cancer tissues and that its increased expression predicted a good prognosis. Elevated CHOP contributed to destruction of LAMTOR5-induced apoptotic suppression and proliferation. Mechanistically, LAMTOR5-recruited DNA methyltransferase 1 (DNMT1) to the CpG3 region (-559/-429) of the CHOP promoter and potentiated its hypermethylation to block its interaction with general transcription factor IIi (TFII-I), resulting in its inactivation. Moreover, LAMTOR5-enhanced miR-182/miR-769 reduced CHOP expression by targeting its 3'UTR. Notably, lenvatinib, a first-line targeted therapy for liver cancer, could target the LAMTOR5/CHOP axis to prevent liver cancer progression. Accordingly, LAMTOR5-mediated silencing of CHOP via the regulation of ER stress-related apoptosis promotes liver cancer growth, providing a theoretical basis for the use of lenvatinib for the treatment of liver cancer.

HBXIP induces PARP1 via WTAP-mediated m6A modification and CEBPA-activated transcription in cisplatin resistance to hepatoma.

Poly (ADP-ribose) polymerase 1 (PARP1) is a DNA-binding protein that is involved in various biological functions, including DNA damage repair and transcription regulation. It plays a crucial role in cisplatin resistance. Nevertheless, the exact regulatory pathways governing PARP1 have not yet been fully elucidated. In this study, we present evidence suggesting that the hepatitis B X-interacting protein (HBXIP) may exert regulatory control over PARP1. HBXIP functions as a transcriptional coactivator and is positively associated with PARP1 expression in tissues obtained from hepatoma patients in clinical settings, and its high expression promotes cisplatin resistance in hepatoma. We discovered that the oncogene HBXIP increases the level of PARP1 m6A modification by upregulating the RNA methyltransferase WTAP, leading to the accumulation of the PARP1 protein. In this process, on the one hand, HBXIP jointly activates the transcription factor ETV5, promoting the activation of the WTAP promoter and further facilitating the promotion of the m6A modification of PARP1 by WTAP methyltransferase, enhancing the RNA stability of PARP1. On the other hand, HBXIP can also jointly activate the transcription factor CEBPA, enhance the activity of the PARP1 promoter, and promote the upregulation of PARP1 expression, ultimately leading to enhanced DNA damage repair capability and promoting cisplatin resistance in hepatoma. Notably, aspirin inhibits HBXIP, thereby reducing the expression of PARP1. Overall, our research revealed a novel mechanism for increasing PARP1 abundance, and aspirin therapy could overcome cisplatin resistance in hepatoma.

Nomogram for preoperative estimation of microvascular invasion risk in hepatocellular carcinoma.

Microvascular invasion (MVI) is an adverse prognostic indicator of tumor recurrence after surgery for hepatocellular carcinoma (HCC). Therefore, developing a nomogram for estimating the presence of MVI before liver resection is necessary. We retrospectively included 260 patients with pathologically confirmed HCC at the Fifth Medical Center of Chinese PLA General Hospital between January 2021 and April 2024. The patients were randomly divided into a training cohort (n = 182) for nomogram development, and a validation cohort (n = 78) to confirm the performance of the model (7:3 ratio). Significant clinical variables associated with MVI were then incorporated into the predictive nomogram using both univariate and multivariate logistic analyses. The predictive performance of the nomogram was assessed based on its discrimination, calibration, and clinical utility. Serum carnosine dipeptidase 1 ([CNDP1] OR 2.973; 95 % CI 1.167-7.575; p = 0.022), cirrhosis (OR 8.911; 95 % CI 1.922-41.318; p = 0.005), multiple tumors (OR 4.095; 95 % CI 1.374-12.205; p = 0.011), and tumor diameter ≥3 cm (OR 4.408; 95 % CI 1.780-10.919; p = 0.001) were independent predictors of MVI. Performance of the nomogram based on serum CNDP1, cirrhosis, number of tumors and tumor diameter was achieved with a concordance index of 0.833 (95 % CI 0.771-0.894) and 0.821 (95 % CI 0.720-0.922) in the training and validation cohorts, respectively. It fitted well in the calibration curves, and the decision curve analysis further confirmed its clinical usefulness. The nomogram, incorporating significant clinical variables and imaging features, successfully predicted the personalized risk of MVI in HCC preoperatively.

Disulfiram mediated anti-tumour effect in pituitary neuroendocrine tumours by inducing cuproptosis.

CONTEXT: Medical treatment plays a critical role in pituitary neuroendocrine tumour (PitNET) treatment. Dopamine agonists and somatostatin receptor agonists are the only known drugs for effectively treating PitNET. Thus, the identification of potential therapeutic targets and drugs is urgently needed. OBJECTIVE: To discover potential drugs that can suppress PitNET growth and to further investigate the underlying mechanism involved. METHODS: High-throughput drug screening of primary cultures of 17 patient-derived PitNETs was performed to identify potential therapeutic compounds. Cell viability assays, Western blot analysis and flow cytometry were used to investigate pituitary neuroendocrine tumour cell lines and patient-derived PitNET cultures in vitro. In vivo drug efficacy was examined in a mouse xenograft model. RESULTS: Seventeen primary PitNET samples were collected for high-throughput drug screening, and a class of copper ionophores that can effectively inhibit cell growth, such as zinc pyrithione, elesclomol, and disulfiram (DSF), was identified. Subsequent experiments initially validated the dose-dependent cell growth-suppressing effect of these copper ionophores on AtT20, GH3, and MMQ cells and several primary PitNET cell lines. Moreover, we confirmed that the cytotoxic effect of DSF depends on the presence of copper. Additionally, we determined that cell death occurs via cuproptosis, with events such as Fe-S cluster protein loss, dihydrolipoyl transacetylase oligomerization and heat shock protein 70 upregulation. Finally, we verified the cytotoxic effects of DSF in vivo. CONCLUSION: The present study revealed copper ionophores as a potential class of drugs for PitNET treatment. DSF induced PitNET cell death via cuproptosis and might be a promising option for PitNET therapy.

Triglyceride-glucose index and health outcomes: an umbrella review of systematic reviews with meta-analyses of observational studies.

BACKGROUND: Numerous meta-analyses have explored the association between the triglyceride-glucose (TyG) index and diverse health outcomes, yet the comprehensive assessment of the scope, validity, and quality of this evidence remains incomplete. Our aim was to systematically review and synthesise existing meta-analyses of TyG index and health outcomes and to assess the quality of the evidence. METHODS: A thorough search of PubMed, EMBASE, and Web of Science databases was conducted from their inception through to 8 April 2024. We assessed the quality of reviews using A Measurement Tool to Assess Systematic Reviews (AMSTAR) and the certainty of the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. This study was registered with PROSPERO (CRD: 42024518587). RESULTS: Overall, a total of 95 associations from 29 meta-analyses were included, investigating associations between TyG index and 30 health outcomes. Of these, 83 (87.4%) associations were statistically significant (P < 0.05) according to the random effects model. Based on the AMSTAR tool, 16 (55.2%) meta-analyses were high quality and none was low quality. The certainty of the evidence, assessed by the GRADE framework, showed that 6 (6.3%) associations were supported by moderate-quality evidence. When compared with the lowest category of the TyG index, the risk of contrast-induced nephropathy (CIN) [relative risk (RR) = 2.25, 95%CI 1.82, 2.77], the risk of stroke in patients with diabetes mellitus (RR = 1.26, 95%CI 1.18, 1.33) or with acute coronary syndrome disease (RR = 1.56, 95%CI 1.06, 2.28), the prognosis of coronary artery disease (CAD)-non-fatal MI (RR = 2.02, 95%CI 1.32, 3.10), and the severity of CAD including coronary artery stenosis (RR = 3.49, 95%CI 1.71, 7.12) and multi-vessel CAD (RR = 2.33, 95%CI 1.59, 3.42) increased with high TyG index. CONCLUSION: We found that the TyG index was positively associated with many diseases including the risk of CIN and stroke, the prognosis of CAD, and the severity of CAD which were supported by moderate-quality evidence. TyG index might be useful to identify people at high-risk for developing these diseases.