Molecular targets and mechanisms of different aberrant alternative splicing in metastatic liver cancer.

Metastasis remains a major challenge in the successful management of malignant diseases. The liver is a major site of metastatic disease and a leading cause of death from gastrointestinal malignancies such as colon, stomach, and pancreatic cancers, as well as melanoma, breast cancer, and sarcoma. As an important factor that influences the development of metastatic liver cancer, alternative splicing drives the diversity of RNA transcripts and protein subtypes, which may provide potential to broaden the target space. In particular, the dysfunction of splicing factors and abnormal expression of splicing variants are associated with the occurrence, progression, aggressiveness, and drug resistance of cancers caused by the selective splicing of specific genes. This review is the first to provide a detailed summary of the normal splicing process and alterations that occur during metastatic liver cancer. It will cover the role of alternative splicing in the mechanisms of metastatic liver cancer by examining splicing factor changes, abnormal splicing, and the contribution of hypoxia to these changes during metastasis.

Comparative efficacy of telehealth interventions on promoting cancer screening: A network meta-analysis of randomized controlled trials.

BACKGROUND: Cancer screening is a pivotal method for reducing mortality from disease, but the screening coverage is still lower than expected. Telehealth interventions demonstrated significant benefits in cancer care, yet there is currently no consensus on their impact on facilitating cancer screening or on the most effective remote technology. DESIGN: A network meta-analysis was conducted to detect the impact of telehealth interventions on cancer screening and to identify the most effective teletechnologies. METHODS: Six English databases were searched from inception until July 2023 to yield relevant randomized controlled trials (RCTs). Two individual authors completed the literature selection, data extraction, and methodological evaluations using the Cochrane Risk of Bias tool. Traditional pairwise analysis and network meta-analysis were performed to identify the overall effects and compare different teletechnologies. RESULTS: Thirty-four eligible RCTs involving 131,644 participants were enrolled. Overall, telehealth interventions showed statistically significant effects on the improvement of cancer screening. Subgroup analyses revealed that telehealth interventions were most effective for breast and cervical cancer screening, and rural populations also experienced benefits, but there was no improvement in screening for older adults. The network meta-analysis indicated that mobile applications, video plus telephone, and text message plus telephone were associated with more obvious improvements in screening than other teletechnologies. CONCLUSION: Our study identified that telehealth interventions were effective for the completion of cancer screening and clarified the exact impact of telehealth on different cancer types, ages, and rural populations. Mobile applications, video plus telephone, and text message plus telephone are the three forms of teletechnologies most likely to improve cancer screening. More well-designed RCTs involving direct comparisons of different teletechnologies are needed in the future. CLINICAL RELEVANCE: Telehealth interventions should be encouraged to facilitate cancer screening, and the selection of the optimal teletechnology based on the characteristics of the population is also necessary.

Next-generation anti-PD-L1/IL-15 immunocytokine elicits superior antitumor immunity in cold tumors with minimal toxicity.

The clinical applications of immunocytokines are severely restricted by dose-limiting toxicities. To address this challenge, here we propose a next-generation immunocytokine concept involving the design of LH05, a tumor-conditional anti-PD-L1/interleukin-15 (IL-15) prodrug. LH05 innovatively masks IL-15 with steric hindrance, mitigating the "cytokine sink" effect of IL-15 and reducing systemic toxicities associated with wild-type anti-PD-L1/IL-15. Moreover, upon specific proteolytic cleavage within the tumor microenvironment, LH05 releases an active IL-15 superagonist, exerting potent antitumor effects. Mechanistically, the antitumor efficacy of LH05 depends on the increased infiltration of CD8+ T and natural killer cells by stimulating the chemokines CXCL9 and CXCL10, thereby converting cold tumors into hot tumors. Additionally, the tumor-conditional anti-PD-L1/IL-15 can synergize with an oncolytic virus or checkpoint blockade in advanced and metastatic tumor models. Our findings provide a compelling proof of concept for the development of next-generation immunocytokines, contributing significantly to current knowledge and strategies of immunotherapy.

Identification of WNK1 as a therapeutic target to suppress IgH/MYC expression in multiple myeloma.

Multiple myeloma (MM) remains an incurable hematological malignancy demanding innovative therapeutic strategies. Targeting MYC, the notorious yet traditionally undruggable oncogene, presents an appealing avenue. Here, using a genome-scale CRISPR-Cas9 screen, we identify the WNK lysine-deficient protein kinase 1 (WNK1) as a regulator of MYC expression in MM cells. Genetic and pharmacological inhibition of WNK1 reduces MYC expression and, further, disrupts the MYC-dependent transcriptional program. Mechanistically, WNK1 inhibition attenuates the activity of the immunoglobulin heavy chain (IgH) enhancer, thus reducing MYC transcription when this locus is translocated near the MYC locus. WNK1 inhibition profoundly impacts MM cell behaviors, leading to growth inhibition, cell-cycle arrest, senescence, and apoptosis. Importantly, the WNK inhibitor WNK463 inhibits MM growth in primary patient samples as well as xenograft mouse models and exhibits synergistic effects with various anti-MM compounds. Collectively, our study uncovers WNK1 as a potential therapeutic target in MM.

Quality of life and its related-influencing factors in patients with cervical cancer based on the scale QLICP-CE(V2.0).

BACKGROUND: Quality of life research can guide clinical workers to adopt more targeted treatment and intervention measures, so as to achieve the purpose of improving patients' quality of life. The objective of this study was to evaluate health-related quality of life in Chinese patients with cervical cancer and to explore its influencing factors. METHODS: A total of 186 patients with cervical cancer were investigated by using the QLICP-CE (V2.0) scale (Quality of Life Instruments for Cancer Patients-Cervical Cancer) developed by our group in China. The data were analyzed by t-test, one-way ANOVA, univariate analysis, and multivariate linear regression. RESULTS: The total score of quality of life scale for cervical cancer patients was (62.58 ± 12.69), Univariate analysis of objective clinical indexes showed that creatinine concentration was a negative influence factor in the psychological domain, potassium ion concentration was a negative influence factor in the common symptoms and side effect domain, erythrocyte content was a positive influence factor physical domain and common general domain. Multiple linear regression results suggested that clinical staging was the influencing factor of common symptom and side effect domain, common general module and total score of scale. Marital status has different degrees of influence on the psychological, social, and common general domains. The level of education also influenced scores in the social domain. CONCLUSION: The total score of quality of life in patients with cervical cancer who received active treatment was acceptable. Marital status, clinical staging, and educational level are the factors that affect the quality of life of patients with cervical cancer. At the same time, potassium ion concentration, red blood cell count and creatinine concentration also have important effects on quality of life in patients with cervical cancer. Therefore, it is very important to give personalized treatment and nursing to patients based on various factors.

Individualized management of immunosuppressants in liver transplant recipients by using a novel immune score system.

BACKGROUND: There is no reliable means to evaluate the immune status of liver transplant recipients. We proposed a novel score model, namely Mingdao immune cell analysis and Mingdao immune score system, to quantify the immunity. METHODS: Data from those who underwent a single liver transplant between January 2017 and June 2020 at Beijing Chaoyang Hospital, were collected. In addition, healthy volunteers were also enrolled. The score model was based on the immune cell populations determined by flow cytometry. RESULTS: There were a total of 376 healthy controls with 376 tests and 148 liver transplant recipients with 284 tests in this study. Evaluated by Mingdao immune cell analysis and Mingdao immune score system, the mean scores of healthy controls were near zero suggesting a balanced immune system. In contrast, the mean scores of liver transplant recipients were negative both before and after surgery indicating a compromised immune system. When liver transplant recipients were given a reduced or routine first dose according to their preoperative score, they had similar recovery of liver function. Moreover, liver transplant recipients with increased scores ≥ 5 were associated with elevated aspartate transaminase and alanine amiotransferase. Finally, on multivariate analysis the score model was the only significant independent risk factor for clinical acute rejection (P = 0.021; Odds ratio, 0.913; 95% confidence interval, 0.845-0.987). CONCLUSION: The novel score model could be used as an indicator to reflect immunity and to regulate immunosuppressants in liver transplant recipients after surgery.

[Effect and mechanism of Maxing Shigan Decoction on reducing inflammatory response in rats with cough variant asthma via TLR4/MyD88/NF-κB and p38 MAPK signaling pathways].

This study aims to investigate the effect and mechanism of Maxingshigan Decoction on inflammation in the rat model of cough variant asthma(CVA). The SPF-grade SD rats of 6-8 weeks were randomized into normal, model, Montelukast sodium, and low-, medium-, and high-dose Maxing Shigan Decoction groups, with 8 rats in each group. The CVA rat model was induced by ovalbumin(OVA) and aluminum hydroxide sensitization and ovalbumin stimulation. The normal group and model group were administrated with equal volume of normal saline by gavage, and other groups with corresponding drugs by gavage. After the experiment, the number of white blood cells in blood and the levels of interleukin-6(IL-6), interleukin-10(IL-10), and tumor necrosis factor-α(TNF-α) in the serum were measured. The lung tissue was stained with hematoxylin-eosin(HE). Western blot was employed to determine the protein levels of nuclear factor-κB(NF-κB), Toll-like receptor 4(TLR4), myeloid differentiation protein(MyD88), and mitogen-activated protein kinase(MAPK) in the lung tissue. Real-time PCR was carried out to measure the mRNA levels of TLR4 and MyD88 in the lung tissue. Compared with the normal group, the model group showed increased white blood cells, elevated IL-6 and TNF-α levels(P<0.01), lowered IL-10 level(P<0.01), up-regulated protein levels of TLR4, MyD88, p-p65/NF-κB p65, and p-p38 MAPK/p38 MAPK(P<0.01) and mRNA levels of TLR4 and MyD88(P<0.01) in the lung tissue. HE staining showed obvious infiltration of inflammatory cells around the airway and cell disarrangement in the model group. Compared with the model group, Montelukast sodium and high-dose Maxing Shigan Decoction reduced the white blood cells, lowered the IL-6 and TNF-α levels(P<0.01), and elevated the IL-10 level(P<0.01). Moreover, they down-regulated the protein levels of TLR4, MyD88, p-p65/NF-κB p65, p-p38 MAPK/p38 MAPK in the lung tissue(P<0.01) and the mRNA levels of TLR4 and MyD88 in the lung tissue(P<0.01). HE staining showed that Montelukast sodium and high-dose Maxing Shigan Decoction reduced inflammatory cell infiltration and cell disarrangement. The number of white blood cells, the levels of IL-10 and TNF-α in the serum, the protein levels of TLR4, MyD88, p-p65/NF-κB p65, and p-p38 MAPK/p38 MAPK, and the mRNA levels of TLR4 and MyD88 in the lung tissue showed no significant differences between the Montelukast sodium group and high-dose Maxing Shigan Decoction group. Maxing Shigan Decoction can inhibit airway inflammation in CVA rats by inhibiting the activation of TLR4/MyD88/NF-κB and p38 MAPK signaling pathways.

FOXP2 inhibits the aggressiveness of lung cancer cells by blocking TGFß signaling.

Lung cancer is associated with high morbidity and mortality rates. Forkhead box P2 (FOXP2) functions as an antitumor gene in various cancers. However, its role in lung cancer remains to be elucidated. The present study explored the potential role of FOXP2 in lung cancer. mRNA levels and protein expression were determined using RT-qPCR and western blotting, respectively. Functional analysis was performed using the CCK-8, Transwell and TUNEL assays. FOXP2 expression was downregulated in lung cancer. Notably, FOXP2 suppressed the proliferative, migratory and invasive abilities of lung cancer cells and promoted tumor cell apoptosis. In addition, FOXP2 blocked TGFß signaling. However, SRI-011381-stimulated activation of TGFß signaling reversed the effects of overexpressed FOXP2 and promoted the aggressiveness of lung cancer cells. FOXP2 functions as an antitumor gene in lung cancer cells. FOXP2 suppressed the malignant behavior of lung cancer by inactivating TGFß signaling.

Precision medicine in colorectal cancer: Leveraging multi-omics, spatial omics, and artificial intelligence.

Colorectal cancer (CRC) is a leading cause of cancer-related deaths. Recent advancements in genomic technologies and analytical approaches have revolutionized CRC research, enabling precision medicine. This review highlights the integration of multi-omics, spatial omics, and artificial intelligence (AI) in advancing precision medicine for CRC. Multi-omics approaches have uncovered molecular mechanisms driving CRC progression, while spatial omics have provided insights into the spatial heterogeneity of gene expression in CRC tissues. AI techniques have been utilized to analyze complex datasets, identify new treatment targets, and enhance diagnosis and prognosis. Despite the tumor's heterogeneity and genetic and epigenetic complexity, the fusion of multi-omics, spatial omics, and AI shows the potential to overcome these challenges and advance precision medicine in CRC. The future lies in integrating these technologies to provide deeper insights and enable personalized therapies for CRC patients.

A novel cancer-germline gene DAZL promotes progression and cisplatin resistance of non-small cell lung cancer by upregulating JAK2 and MCM8.

Germline-specific genes are usually activated in cancer cells and drive cancer progression; such genes are called cancer-germline or cancer-testis genes. The RNA-binding protein DAZL is predominantly expressed in germ cells and plays a role in gametogenesis as a translational activator or repressor. However, its expression and role in non-small cell lung cancer (NSCLC) are unknown. Here, mining of RNA-sequencing data from public resources and immunohistochemical analysis of tissue microarrays showed that DAZL was expressed exclusively in testis among normal human tissues but ectopically expressed in NSCLC tissues. Testis and NSCLC cells expressed the shorter and longer transcript variants of the DAZL gene, respectively. Overexpression of the longer DAZL transcript promoted tumor growth in a mouse xenograft model. Silencing of DAZL suppressed cell proliferation, colony formation, migration, invasion, and cisplatin resistance in vitro and tumor growth in vivo. Quantitative proteomic analysis based on tandem mass tag and Western blot analysis showed that DAZL upregulated the expression of JAK2 and MCM8. RNA-binding protein immunoprecipitation assays showed that DAZL bound to the mRNA of JAK2 and MCM8. The JAK2 inhibitor fedratinib attenuated the oncogenic outcomes induced by DAZL overexpression, whereas silencing MCM8 counteracted the effects of DAZL overexpression on cisplatin-damaged DNA synthesis and half-maximal inhibitory concentration of cisplatin. In conclusion, DAZL was identified as a novel cancer-germline gene that enhances the translation of JAK2 and MCM8 to promote NSCLC progression and resistance to cisplatin, respectively. These findings suggest that DAZL is a potential therapeutic target in NSCLC.

Sophoridine exerts anti-arthritic effects on fibroblast-like synoviocytes and collagen-induced arthritis in rats.

The discovery of alternative medicines with fewer adverse effects is urgently needed for rheumatoid arthritis (RA). Sophoridine (SR), the naturally occurring quinolizidine alkaloid isolated from the leguminous sophora species, has been demonstrated to possess a wide range of pharmacological activities. However, the effect of SR on RA remains unknown. In this study, the collagen-induced arthritis (CIA) rat model and tumor necrosis factor alpha (TNFα)-induced fibroblast-like synoviocytes (FLSs) were utilized to investigate the inhibitory effect of SR on RA. The anti-arthritic effect of SR was evaluated using the CIA rat model in vivo and TNFα-stimulated FLSs in vitro. Mechanistically, potential therapeutic targets and pathways of SR in RA were analyzed through drug target databases and disease databases, and validation was carried out through immunofluorescence, immunohistochemistry, and Western blot. The in vivo results revealed that SR treatment effectively ameliorated synovial inflammation and bone erosion in rats with CIA. The in vitro studies showed that SR could significantly suppress the proliferation and migration in TNFα-induced arthritic FLSs. Mechanistically, SR treatment efficiently inhibited the activation of MAPKs (JNK and p38) and NF-κB pathways in TNFα-induced arthritic FLSs. These findings were further substantiated by Immunohistochemistry results in the CIA rat. SR exerts an anti-arthritic effect in CIA rats through inhibition of the pathogenic characteristic of arthritic FLSs via suppressing NF-κB and MAPKs (JNK and p38) signaling pathways. SR may have a great potential for development as a novel therapeutic agent for RA treatment.

Comparison of the perioperative outcomes of robot-assisted laparoscopic transperitoneal versus retraperitoneal partial nephrectomy for posterior-lateral renal tumors: a systematic review and meta-analysis.

The study aims to assess the available literature and compare the perioperative outcomes of robotic-assisted partial nephrectomy (RAPN) for posterior-lateral renal tumors using transperitoneal (TP) and retroperitoneal (RP) approaches. Systematically searched the Embase, PubMed, and Cochrane Library databases for literature. Eligible studies were those that compared TP-RAPN and RP-RAPN for posterior-lateral renal tumors. The data from the included studies were analyzed and summarized using Review Manager 5.3, which involved comparing baseline patient and tumor characteristics, intraoperative and postoperative outcomes, and oncological outcomes. The analysis included five studies meeting the inclusion criteria, with a total of 1440 patients (814 undergoing RP-RAPN and 626 undergoing TP-RAPN). Both groups showed no significant differences in age, gender, BMI, R.E.N.A.L. score, and tumor size. Notably, compared to TP-RAPN, the RP-RAPN group demonstrated shorter operative time (OT) (MD: 17.25, P = 0.01), length of hospital stay (LOS) (MD: 0.37, P < 0.01), and lower estimated blood loss (EBL) (MD: 15.29, P < 0.01). However, no significant differences were found between the two groups in terms of warm ischemia time (WIT) (MD: -0.34, P = 0.69), overall complications (RR: 1.25, P = 0.09), major complications (the Clavien-Dindo classification ≥ 3) (RR: 0.97, P = 0.93), and positive surgical margin (PSM) (RR: 1.06, P = 0.87). The systematic review and meta-analysis suggests RP-RAPN may be more advantageous for posterior-lateral renal tumors in terms of OT, EBL, and LOS, but no significant differences were found in WIT, overall complications, major complications, and PSM. Both surgical approaches are safe, but a definitive advantage remains uncertain.

Laparoscopic treatment of a patient with multiple organ dysfunction syndrome induced by necrotising fasciitis.

Necrotising fasciitis (NF) is an uncommon surgical emergency that threatens the life and health of patients. We report the treatment of a 76-year-old female patient with NF. The patient developed NF due to chronic poor glycaemic control, which further progressed to multiple organ dysfunction syndrome due to the severity of the hyperglycaemia. After resuscitation at the intensive care unit, surgical treatment was recommended and the patient underwent laparoscopic surgery. She had an uneventful post-operative recovery with aggressive anti-inflammatory therapy, glycaemic control and systemic nutritional support. There were no recurrences during the next 6 months of follow-up. NF should be diagnosed and treated as early as possible to gain valuable treatment time for the patient. Laparoscopic surgery is a treatment option.

Catalytic Hydrogenolysis by Atomically Dispersed Iron Sites Embedded in Chemically and Redox Non-innocent N-Doped Carbon.

Atomically dispersed first-row transition metals embedded in nitrogen-doped carbon materials (M-N-C) show promising performance in catalytic hydrogenation but are less well-studied for reactions with more complex mechanisms, such as hydrogenolysis. Their ability to catalyze selective C-O bond cleavage of oxygenated hydrocarbons such as aryl alcohols and ethers is enhanced with the participation of ligands directly bound to the metal ion as well as longer-range contributions from the support. In this article, we describe how Fe-N-C catalysts with well-defined local structures for the Fe sites catalyze C-O bond hydrogenolysis. The reaction is facilitated by the N-C support. According to spectroscopic analyses, the as-synthesized catalysts contain mostly pentacoordinated FeIII sites, with four in-plane nitrogen donor ligands and one axial hydroxyl ligand. In the presence of 20 bar of H2 at 170-230 °C, the hydroxyl ligand is lost when N4FeIIIOH is reduced to N4FeII, assisted by the H2 chemisorbed on the support. When an alcohol binds to the tetracoordinated FeII sites, homolytic cleavage of the O-H bond is accompanied by reoxidation to FeIII and H atom transfer to the support. The role of the N-C support in catalytic hydrogenolysis is analogous to the behavior of chemically and redox-non-innocent ligands in molecular catalysts based on first-row transition metal ions and enhances the ability of M-N-Cs to achieve the types of multistep activations of strong bonds needed to upgrade renewable and recycled feedstocks.

miR-26a-5p inhibits the proliferation of psoriasis-like keratinocytes in vitro and in vivo by dual interference with the CDC6/CCNE1 axis.

Psoriasis is a chronic inflammatory proliferative dermatological ailment that currently lacks a definitive cure. Employing data mining techniques, this study identified a collection of substantially downregulated miRNAs (top 10). Notably, 32 targets were implicated in both the activation of the IL-17 signaling pathway and cell cycle dysregulation. In silico analysis revealed that one of these miRNAs, miR-26a-5p, is a highly conserved cross-species miRNA. Strikingly, the miR-26a-5p sequences in humans and mice are identical, and mmu-miR-26a-5p was found to target the same 7 cell cycle targets as its human counterpart, hsa-miR-26a-5p. Among these targets, CDC6 and CCNE1 were the most effective targets of miR-26a-5p, which was further validated in vitro using a dual luciferase reporter system and qPCR assay. The therapeutic assessment of miR-26a-5p revealed its remarkable efficacy in inhibiting the proliferation and G1/S transition of keratinocytes (HaCaT and HEKs) in vitro. In vivo experiments corroborated these findings, demonstrating that miR-26a-5p effectively suppressed imiquimod (IMQ)-induced psoriasis-like skin lesions in mice over an 8-day treatment period. Histological analysis via H&E staining revealed that miR-26a-5p treatment resulted in reduced keratinocyte thickness and immune cell infiltration into the spleens of IMQ-treated mice. Mechanistic investigations revealed that miR-26a-5p induced a cascade of downregulated genes associated with the IL-23/IL-17A axis, which is known to be critical in psoriasis pathogenesis, while concomitantly suppressing CDC6 and CCNE1 expression. These findings were corroborated by qPCR and Western blot analyses. Collectively, our study provides compelling evidence supporting the therapeutic potential of miR-26a-5p as a safe and reliable endogenous small nucleic acid for the treatment of psoriasis.

Development of High-Performance Iron-Based Phosphate Cathodes toward Practical Na-Ion Batteries.

Iron-based phosphate cathode of Na4Fe3(PO4)2(P2O7) has been regarded as a low-cost and structurally stable cathode material for Na-ion batteries (NIBs). However, their practical application is greatly hindered by the insufficient electrochemical performance and limited energy density. Here, we report a new iron-based phosphate cathode of Na4.5Fe3.5(PO4)2.5(P2O7) with the intergrown heterostructure of the maricite-type NaFePO4 and orthorhombic Na4Fe3(PO4)2(P2O7) phases at a mole ratio of 0.5:1. Benefited from the increased composition ratio and the spontaneous activation of the maricite-type NaFePO4 phase, the as-prepared Na4.5Fe3.5(PO4)2.5(P2O7) composites deliver a reversible capacity over 130 mA h g-1 and energy density close to 400 W h kg-1, which is far beyond that of the single-phase Na4Fe3(PO4)2(P2O7) cathode (∼120 mA h g-1 and ∼350 W h kg-1). Moreover, the kg-level products from the scale-up synthesis demonstrate a stable cycling performance over 2000 times at 3 C in pouch cells. We believe that our findings could show the way forward the practical application of the iron-based phosphate cathodes for NIBs.

Potential Exploration of Biocompatible Carbon-Coated MoSe2 Nanoparticles for Exploration of the Photothermal Potential in the Treatment of Human Choriocarcinoma.

Background: Molybdenum diselenide (MoSe2), as a nano near-infrared absorber, has been widely studied in the field of photothermal therapy of cancer. However, there is little research on its application in the treatment of human choriocarcinoma. Methods and Results: In this paper, a new type of carbon-coated MoSe2 (MEC) nanoparticles was prepared by a one-step hydrothermal method. The chemical characterization including SEM, TEM, EDS, XRD, FT-IR, TGA, Roman, and XPS showed that MEC was successfully synthesized. MEC exhibited a high photothermal conversion efficiency (50.97%) and extraordinary photothermal stability under laser irradiation. The cell experiment results showed that MEC had good biocompatibility on normal cells while significant photothermal effect on human choriocarcinoma (JEG-3) cells, achieving a good anticancer effect. The level of reactive oxygen species (ROS) in JEG-3 cells was significantly increased under the combination of MEC nanoparticles and near-infrared radiation. MEC nanoparticles could induce apoptosis of JEG-3 cells in combination with near-infrared radiation. Finally, transcriptomic analysis verified that MEC combined with laser radiation could inhibit DNA replication and induce apoptosis, thus improving its therapeutic effect on human choriocarcinoma. Conclusion: MEC nanoparticles exert an excellent photothermal effect and may become an important candidate drug for the treatment of human choriocarcinoma.

Efficacy of nonpharmacological interventions for severe radiation-induced oral mucositis among head and neck cancer patients: A network meta-analysis of randomised controlled trials.

AIMS AND OBJECTIVES: To assess the effectiveness of different nonpharmacological treatments for severe radiation-induced oral mucositis in patients with head and neck cancer. BACKGROUND: Radiation-induced oral mucositis is highly prevalent in patients with head and neck cancer. Current medications for radiation-induced oral mucositis are limited in effectiveness and susceptible to side effects, and while there is an increasing adoption of nonpharmacological interventions, the optimal one remains unclear. DESIGN: Systematic review and network meta-analysis based on the PRISMA-NMA guidelines. METHODS: Six databases were searched. Two authors independently performed the literature screening, data extraction and methodological quality assessment of the included studies. Traditional pairwise meta-analysis was performed by R Studio. A network meta-analysis was then conducted to assess the effects of nonpharmacological interventions for severe radiation-induced oral mucositis in patients with head and neck cancer. RESULTS: Fifty-two studies involving seven types of nonpharmacological interventions were enrolled. The network meta-analysis indicated that natural plant-based therapies might be the most effective, health education interventions might be the second most effective, and honey might be the third most effective interventions for reducing the incidence of severe radiation-induced oral mucositis. For reducing the incidence of severe oral mucositis-related pain, the pairwise meta-analysis showed that only natural plant-based therapies and health education interventions were effective. CONCLUSIONS: Nonpharmacological interventions are effective in the management of severe radiation-induced oral mucositis among patients with head and neck cancer. RELEVANCE TO CLINICAL PRACTICE: Nonpharmacological interventions are a category of safe and effective adjunctive therapies that should be encouraged in clinical practice. TRIAL REGISTRATION DETAILS: CRD42023400745.

Risks and Clinical Predictors of Hepatocellular Carcinoma in Chinese Populations: A Real-World Study of 10,359 Patients in Six Medical Centers.

Purpose: Early detection of hepatocellular carcinoma (HCC) through surveillance could reduce this cancer-associated mortality. We aimed to develop and validate algorithms using panel serum biomarkers to identify HCC in a real-world multi-center study in China. Patients and Methods: A total of 10,359 eligible subjects, including HCCs and benign liver diseases (BLDs), were recruited from six Chinese medical centers. The three nomograms were built using logistic regression and their sensitivities and specificities were carefully assessed in training and validation cohorts. HCC patients after surgical resection were followed to determine the prognostic values of these algorithms. Prospective surveillance performance was assessed in a cohort of chronic hepatitis B patients during 144 weeks follow-up. Results: Independent risk factors such as alpha-fetoprotein (AFP), lens cuinaris agglutinin-reactive fraction of AFP (AFP-L3), des-gamma-carboxy prothrombin (DCP), albumin (ALB), and total bilirubin (TBIL) obtained from train cohort were used to construct three nomograms (LAD, C-GALAD, and TAGALAD) using logistic regression. In the training and two validation cohorts, their AUCs were all over 0.900, and the higher AUCs appeared in TAGALAD and C-GALAD. Furthermore, the three nomograms could effectively stratify HCC into two groups with different survival and recurrence outcomes in follow-up validation. Notably, TAGALAD could predict HCC up to 48 weeks (AUC: 0.984) and 24 weeks (AUC: 0.900) before clinical diagnosis. Conclusion: The proposed nomograms generated from real-world Chinese populations are effective and easy-to use for HCC surveillance, diagnosis, as well as prognostic evaluation in various clinical scenarios based on data feasibility.

A cuproptosis-related gene expression signature predicting clinical prognosis and immune responses in intrahepatic cholangiocarcinoma detected by single-cell RNA sequence analysis.

BACKGROUND: Cholangiocarcinoma represents a malignant neoplasm originating from the hepatobiliary tree, with a subset of tumors developing inside the liver. Intrahepatic cholangiocarcinomas (ICC) commonly exhibit an asymptomatic presentation, rendering both diagnosis and treatment challenging. Cuproptosis, an emerging regulated cell death pathway induced by copper ions, has garnered attention recently. As cancer cells show altered copper metabolism and comparatively higher copper needs, cuproptosis may play a role in the development of ICC. However, studies investigating this possibility are currently lacking. METHODS: Single-cell and bulk RNA sequence data were analyzed, and correlations were established between the expression of cuproptosis-related molecules and ICC patient survival. Genes with predicting survival were used to create a CUPT score using Cox and LASSO regression and tumor mutation burden (TMB) analysis. The CIBERSORT software was employed to characterize immune cell infiltration within the tumors. Furthermore, immune infiltration prediction, biological function enrichment, and drug sensitivity analyses were conducted to explore the potential implications of the cuproptosis-related signature. The effects of silencing solute carrier family 39 member 4 gene (SLC39A4) expression using siRNA were investigated using assays measuring cell proliferation, colony formation, and cell migration. Key genes of cuproptosis were detected by western blotting. RESULTS: The developed CUPT score divided patients into high and low CUPT score groups. Those with a low score had significantly better prognosis and longer survival. In contrast, high CUPT scores were associated with worse clinical outcomes and significantly higher TMB. Comparisons of the two groups also indicated differences in the immune infiltrate present in the tumors. Finally, we were able to identify 95 drugs potentially affecting the cuproptosis pathway. Some of these might be effective in the treatment of ICC. The in vitro experiments revealed that suppressing the expression of SLC39A4 in ICC cell lines resulted in reduced cell proliferation, colony formation, and cell migration. It also led to an increase in cell death and the upregulation of key genes associated with cuproptosis, namely ferredoxin 1 (FDX1) and dihydrolipoyl transacetylase (DLAT). These findings strongly suggest that this cuproptosis-associated molecule may play a pivotal role in the development and metastasis of ICC. CONCLUSIONS: Changes in the expression of a cuproptosis-related gene signature can predict the clinical prognosis of ICC with considerable accuracy. This supports the notion that cuproptosis influences the diversity and complexity of the immune microenvironment, mutational landscape, and biological behavior of ICC. Understanding this pathway better may hold promise for the development of innovative strategies in the management of this disease.