RGF1 controls root meristem size through ROS signalling.

The stem cell niche and the size of the root meristem in plants are maintained by intercellular interactions and signalling networks involving a peptide hormone, root meristem growth factor 1 (RGF1)1. Understanding how RGF1 regulates the development of the root meristem is essential for understanding stem cell function. Although five receptors for RGF1 have been identified2-4, the downstream signalling mechanism remains unknown. Here we report a series of signalling events that follow RGF1 activity. We find that the RGF1-receptor pathway controls the distribution of reactive oxygen species (ROS) along the developmental zones of the Arabidopsis root. We identify a previously uncharacterized transcription factor, RGF1-INDUCIBLE TRANSCRIPTION FACTOR 1 (RITF1), that has a central role in mediating RGF1 signalling. Manipulating RITF1 expression leads to the redistribution of ROS along the root developmental zones. Changes in ROS distribution in turn enhance the stability of the PLETHORA2 protein, a master regulator of root stem cells. Our results thus clearly depict a signalling cascade that is initiated by RGF1, linking this peptide to mechanisms that regulate ROS.

Single-cell RNA sequencing integrated with bulk RNA sequencing analysis identifies a tumor immune microenvironment-related lncRNA signature in lung adenocarcinoma.

BACKGROUND: Recently, long non-coding RNAs (lncRNAs) have been demonstrated as essential roles in tumor immune microenvironments (TIME). Nevertheless, researches on the clinical significance of TIME-related lncRNAs are limited in lung adenocarcinoma (LUAD). METHODS: Single-cell RNA sequencing and bulk RNA sequencing data are integrated to identify TIME-related lncRNAs. A total of 1368 LUAD patients are enrolled from 6 independent datasets. An integrative machine learning framework is introduced to develop a TIME-related lncRNA signature (TRLS). RESULTS: This study identified TIME-related lncRNAs from integrated analysis of single­cell and bulk RNA sequencing data. According to these lncRNAs, a TIME-related lncRNA signature was developed and validated from an integrative procedure in six independent cohorts. TRLS exhibited a robust and reliable performance in predicting overall survival. Superior prediction performance barged TRLS to the forefront from comparison with general clinical features, molecular characters, and published signatures. Moreover, patients with low TRLS displayed abundant immune cell infiltration and active lipid metabolism, while patients with high TRLS harbored significant genomic alterations, high PD-L1 expression, and elevated DNA damage repair (DDR) relevance. Notably, subclass mapping analysis of nine immunotherapeutic cohorts demonstrated that patients with high TRLS were more sensitive to immunotherapy. CONCLUSIONS: This study developed a promising tool based on TIME-related lncRNAs, which might contribute to tailored treatment and prognosis management of LUAD patients.

A novel link between circPDE3B and ferroptosis in esophageal squamous cell carcinoma progression.

AIM: To unravel whether ferroptosis involves with the actions by circPDE3B-mediated facilitation of esophageal squamous cell carcinoma (ESCC) progression. METHODS: Human ESCC tissues and cell lines were prepared for the evaluation of ferroptosis. Cellular iron, ROS, GSH, and MDA levels were measured to assess ferroptosis. Flow cytometry was employed to analyze apoptosis and cell cycle. Subcellular fractionation and fluorescence in situ hybridization (FISH) were conducted to validate the localization of circPDE3B. RNA pull-down, RNA immunoprecipitation (RIP), and luciferase assay were subjected to identify the molecular mechanisms. Nude mouse xenograft model was carried out to evaluate the function of circPDE3B/SLC7A11/CBS in vivo. RESULTS: Increased circPDE3B in human ESCC specimens was positively correlated with ferroptosis-related molecules, SLC7A11 and CBS. Functionally, circPDE3B knockdown triggered ferroptosis, apoptosis, and cell cycle arrest in ESCC cells. Whereas, these effects were obviously blocked by miR-516b-5p inhibitor. Mechanistically, not only circPDE3B sponged miR-516b-5p to upregulate CBS, but also directly bound with HNRNPK to stabilize SLC7A11. In mice, depletion of circPDE3B restrained ESCC growth, while this was abolished by overexpression of CBS or SLC7A11. CONCLUSION: In summary, circPDE3B promotes ESCC progression by suppressing ferroptosis through recruiting HNRNPK/SLC7A11 and miR-516b-5p/CBS axes.

Integrated Exploration of Epigenetic Dysregulation Reveals a Stemness/EMT Subtype and MMP12 Linked to the Progression and Prognosis in Hepatocellular Carcinoma.

Epigenetic dysregulation drives aberrant transcriptional programs playing a critical role in hepatocellular carcinoma (HCC), which may provide novel insights into the heterogeneity of HCC. This study performed an integrated exploration on the epigenetic dysregulation of miRNA and methylation. We discovered and validated three patterns endowed with gene-related transcriptional traits and clinical outcomes. Specially, a stemness/epithelial-mesenchymal transition (EMT) subtype was featured by immune exhaustion and the worst prognosis. Besides, MMP12, a characteristic gene, was highly expressed in the stemness/EMT subtype, which was verified as a pivotal regulator linked to the unfavorable prognosis and further proven to promote tumor proliferation, invasion, and metastasis in vitro experiments. Proteomic analysis by mass spectrometry sequencing also indicated that the overexpression of MMP12 was significantly associated with cell proliferation and adhesion. Taken together, this study unveils innovative insights into epigenetic dysregulation and identifies a stemness/EMT subtype-specific gene, MMP12, correlated with the progression and prognosis of HCC.

Cellular Ligand-Receptor Perturbations Unravel MEIS2 as a Key Factor for the Aggressive Progression and Prognosis in Stage II/III Colorectal Cancer.

Approximately 10-15% of stage II and 25-30% of stage III colorectal cancer (CRC) patients experience recurrence within 5 years after surgery, and existing taxonomies are insufficient to meet the needs of clinical precision treatment. Thus, robust biomarkers and precise management were urgently required to stratify stage II and III CRC and identify potential patients who will benefit from postoperative adjuvant therapy. Alongside, interactions of ligand-receptor pairs point to an emerging direction in tumor signaling with far-reaching implications for CRC, while their impact on tumor subtyping has not been elucidated. Herein, based on multiple large-sample multicenter cohorts and perturbations of the ligand-receptor interaction network, four well-characterized ligand-receptor-driven subtypes (LRDS) were established and further validated. These molecular taxonomies perform with unique heterogeneity in terms of molecular characteristics, immune and mutational landscapes, and clinical features. Specifically, MEIS2, a key LRDS4 factor, performs significant associations with proliferation, invasion, migration, and dismal prognosis of stage II/III CRC, revealing promising directions for prognostic assessment and individualized treatment of CRC patients. Overall, our study sheds novel insights into the implications of intercellular communication on stage II/III CRC from a ligand-receptor interactome perspective and revealed MEIS2 as a key factor in the aggressive progression and prognosis for stage II/III CRC.

Tertiary lymphoid structural heterogeneity determines tumour immunity and prospects for clinical application.

Tertiary lymphoid structures (TLS) are clusters of immune cells that resemble and function similarly to secondary lymphoid organs (SLOs). While TLS is generally associated with an anti-tumour immune response in most cancer types, it has also been observed to act as a pro-tumour immune response. The heterogeneity of TLS function is largely determined by the composition of tumour-infiltrating lymphocytes (TILs) and the balance of cell subsets within the tumour-associated TLS (TA-TLS). TA-TLS of varying maturity, density, and location may have opposing effects on tumour immunity. Higher maturity and/or higher density TLS are often associated with favorable clinical outcomes and immunotherapeutic response, mainly due to crosstalk between different proportions of immune cell subpopulations in TA-TLS. Therefore, TLS can be used as a marker to predict the efficacy of immunotherapy in immune checkpoint blockade (ICB). Developing efficient imaging and induction methods to study TA-TLS is crucial for enhancing anti-tumour immunity. The integration of imaging techniques with biological materials, including nanoprobes and hydrogels, alongside artificial intelligence (AI), enables non-invasive in vivo visualization of TLS. In this review, we explore the dynamic interactions among T and B cell subpopulations of varying phenotypes that contribute to the structural and functional diversity of TLS, examining both existing and emerging techniques for TLS imaging and induction, focusing on cancer immunotherapies and biomaterials. We also highlight novel therapeutic approaches of TLS that are being explored with the aim of increasing ICB treatment efficacy and predicting prognosis.

CT-guided radioactive 125I seeds brachytherapy for lung oligometastases from colorectal cancer: initial results.

OBJECTIVES: To evaluate the safety and effectiveness of computed tomography (CT)-guided radioactive 125I seeds brachytherapy (RISB) for lung oligometastases (LO) from colorectal cancer (CRC). METHODS: Data for 144 LOs from 70 CRC patients who underwent CT-guided RISB were retrospectively analyzed. The primary endpoints were progression-free survival (PFS) and overall survival (OS), and the secondary endpoints were technical success, local control rate (LCR), and complications. Kaplan-Meier method was used for survival analysis. Cox model was used to identify the independent predictors of poor prognosis. RESULTS: The RISB procedures were successfully performed in all patients, and the success rate was 100%. The median follow-up was 27.8 months. The median PFS was 10.0 months (95% CI: 8.9-11.1) and the 1- and 2-year PFS rates were 32.9% and 5.9%, respectively. On multivariate analysis, serum carcinoembryonic antigen (CEA) ≤ 15 ng/ml (P = 0.048), middle-high differentiated pathological classification (P = 0.015), primary TNM stages I-III (P = 0.001), LO number ≤ 2 (P < 0.001) and cumulative gross tumor volume (GTV) ≤ 40 cm3 (P < 0.001) showed superior PFS. The median OS was 30.8 months (95% CI: 27.1-34.4) and the 1-, 2-, and 3-year OS rates were 95.7%, 67.4%, and 42.5%, respectively. On multivariate analysis, serum CEA ≤ 15 ng/ml (P = 0.004), middle-high differentiated pathological classification (P < 0.001), primary TNM stages I-III (P < 0.001), LO number ≤ 2 (P < 0.001), cumulative GTV ≤ 40 cm3 (P < 0.001) and system treatments combined with chemotherapy and target therapy (P < 0.001) showed superior OS. The LCR for 3, 6, and 12 months was 97.9%, 91.0%, and 83.6%, respectively. There were 4 cases of pneumothorax at 5.7% that required drainage. CONCLUSIONS: RISB for LO from CRC is safe and effective, and serum CEA, TNM stage, LO number, cumulative GTV, and system treatments should be emphasized for long OS.

High ratio of resident to exhausted CD4 + T cells predicts favorable prognosis and potentially better immunotherapeutic efficacy in hepatocellular carcinoma.

BACKGROUND: Tumor-infiltrating lymphocytes (TILs) are significantly implicated in regulating the tumor immune microenvironment (TIME) and immunotherapeutic response. However, little is known about the impact of the resident and exhausted status of TILs in hepatocellular carcinoma (HCC). METHODS: Single-cell RNA sequencing data was applied to discover resident and exhausted signatures of TILs. Survival outcomes, biological function, immune infiltration, genomic variation, immunotherapeutic efficacy, and sorafenib response were further explored the clinical significance and molecular association of TILs in HCC. Moreover, a candidate gene with predictive capability for the dismal subtype was identified through univariate Cox regression analysis, survival analysis, and the BEST website. RESULTS: Single-cell analysis revealed that CD8 + T, CD4 + T, and NK cells were strongly associated with resident and exhausted patterns. Specific resident and exhausted signatures for each subpopulation were extracted in HCC. Further multivariate Cox analysis revealed that the ratio of resident to exhausted CD4 + T cells in TIME was an independent prognostic factor. After incorporating tumor purity with the ratio of resident to exhausted CD4 + T cells, we stratified HCC patients into three subtypes and found that (i) CD4 residencyhighexhaustionlow subtype was endowed with favorable prognosis, immune activation, and sensitivity to immunotherapy; (ii) CD4 exhaustionhighresidencylow subtype was characterized by genome instability and sensitivity to sorafenib; (iii) Immune-desert subtype was associated with malignant-related pathways and poor prognosis. Furthermore, spindle assembly abnormal protein 6 homolog (SASS6) was identified as a key gene, which accurately predicted the immune-desert subtype. Prognostic analysis as well as in vitro and in vivo experiments further demonstrated that SASS6 was closely associated with tumor prognosis, proliferation, and migration. CONCLUSIONS: The ratio of resident to exhausted CD4 + T cells shows promise as a potential biomarker for HCC prognosis and immunotherapy response and SASS6 may serve as a biomarker and therapeutic target for prognostic assessment of HCC.

Transcatheter arterial chemoembolization using CalliSpheres beads loaded with arsenic trioxide for unresectable large or huge hepatocellular carcinoma: a prospective study.

OBJECTIVES: To determine the safety and efficacy of transcatheter arterial chemoembolization with CalliSpheres® beads loaded with arsenic trioxide (CBATO-TACE) in the first-line treatment of patients with large (5 cm ≤ maximum diameter < 10 cm) or huge (maximum diameter ≥ 10 cm) hepatocellular carcinoma (HCC). METHODS: Patients were randomly allocated to the CBATO-TACE group and the conventional transcatheter arterial chemoembolization (cTACE) group. The primary endpoint was progression-free survival (PFS). The secondary endpoint was overall survival (OS), treatment response, and treatment-related adverse events (TRAEs). The extrahepatic collateral arteries, liver function, and liver fibrosis after the first TACE were also evaluated. RESULTS: From September 2018 to September 2020, a total of 207 patients who underwent TACE were consecutively enrolled in this study. The median PFS was 9.5 months (range: 8.0 - 11.0) in the CBATO group, which was significantly longer than that in the cTACE group (6.0 months, range: 4.0-6.0) (p < 0.0001). Patients in the CBATO group had a median OS of 22 months (range: 20.0 - 27.0) compared with 16 months (range: 15.0 - 20.0) in the cTACE group (p = 0.0084). The most common TRAEs were fever (p = 0.043), and nausea and vomiting (p = 0.002), which were more observed in the cTACE group. In addition, the progressive disease time, pulmonary metastasis rate (p = 0.01), the mean number of extrahepatic collateral arteries (p = 0.01), and average number of TACE sessions (p = 0.025) were significantly decreased in the CBATO group. CONCLUSIONS: CBATO-TACE achieved better therapeutic outcomes and similar safety profile compared to cTACE in large or huge HCC patients. Furthermore, CBATO-TACE was able to reduce extrahepatic collateral arteries production and extrahepatic lung metastasis. CLINICAL RELEVANCE STATEMENT: Our study showed that CalliSpheres® beads loaded with arsenic trioxide (CBATO-TACE) were effective and safe for the treatment of large and giant HCC. In addition, CBATO-TACE can reduce lateral hepatic branch artery formation and extrahepatic pulmonary metastasis, which provides a new treatment approach for unresectable HCC. KEY POINTS: • We compare long-term efficacy and safety of transcatheter arterial chemoembolization with CalliSpheres® beads loaded with arsenic trioxide (CBATO-TACE) and conventional transcatheter arterial chemoembolization (cTACE) in patients with large (5 cm ≤ maximum diameter < 10 cm) or huge HCC (maximum diameter ≥ 10 cm). • Compared with cTACE, CBATO-TACE significantly improved therapeutic outcomes, overall survival, and progression-free survival in patients with large or huge HCC. The safety assessment suggested that CBATO-TACE is a safe treatment that improves the quality of life and has good treatment adherence.

Percutaneous Nephroureteral Stent Placement and Antegrade Forceps Biopsy of Ureteral Obstruction.

PURPOSE: To evaluate the feasibility of percutaneous transluminal ureteral biopsy (PTUB) combined with percutaneous nephroureteral stent placement for ureteral obstruction under fluoroscopy. MATERIALS AND METHODS: From September 2011 to July 2021, 37 patients (27 men and 10 women; median age, 65.0 years) who experienced ureteroscopic biopsy failure or refused or were unable to undergo ureteroscopic biopsy underwent PTUB for ureteral obstruction during nephroureteral stent placement under fluoroscopic guidance. Data on technical success, early adverse events, and radiation dose were collected. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and overall accuracy (OA) of PTUB were analyzed. RESULTS: The technical success of PTUB was 89.2%, with a mean irradiation dose of 76.9 mGy·cm2 ± 12.2. A total of 67.6% (25/37) of the cases were correctly diagnosed with malignancy, whereas 8 cases were confirmed to be true negatives. There were 4 false negatives and no false positives. PTUB had a sensitivity, specificity, PPV, NPV, and OA of 86.2% (25/29), 100% (8/8), 100% (25/25), 66.7% (8/12), and 89.2% (33/37), respectively. Eleven patients (29.7%) experienced Grade 1 adverse events (transient aggravated hematuria). CONCLUSIONS: PTUB appears to be a safe and effective alternative to ureteroscopic biopsy for ureteral obstruction.

Clinical outcomes of drug-coated balloons dilatation for benign esophageal stricture.

BACKGROUND: Drug-coated balloons (DCBs) angioplasty is safe and effective for coronary artery disease. However, DCBs dilatation for the treatment of benign esophageal strictures is rarely reported. PURPOSE: We aimed to report the clinical outcomes of DCBs dilatation for patients with benign esophageal strictures. METHODS: From May 2020 to August 2023, 18 patients underwent DCBs dilatation for benign esophageal strictures. Baseline demographics were recorded and evaluated, including gender, age, comorbidities, stricture diameter and length, dilatation session, complications. RESULTS: A total of 24 dilatation sessions of DCBs were performed, with a mean of 1.3 ± 0.6 sessions per patients (range 1.0-5.0). Dysphagia score decreased significantly after DCBs dilatation (2.6 ± 1.1 vs. 0.9 ± 1.3, p = 0.0002). Both stricture diameter and stricture index decreased significantly after DCBs dilatation (p < 0.0001). No procedure-related death, massive bleeding or esophageal perforation was observed during or after DCBs dilatation. Minor complications were found in only 3 patients (16.7%). All 18 patients were successfully followed up for a median period of 12.0 months. By the end of follow up, 10 patients showed no dysphagia, 6 patients showed mild dysphagia and 2 patients showed no improvement in dysphagia. The clinical success rate of DCBs dilatation is 88.9%. CONCLUSION: DCBs dilatation may be a safe, effective and feasible treatment for benign esophageal strictures, and can be utilized as an alternative option after standard dilatation has failed. Prospective studies with large samples are needed to further validate its clinical efficacy.

Ferroptosis and EMT: key targets for combating cancer progression and therapy resistance.

Iron-dependent lipid peroxidation causes ferroptosis, a form of regulated cell death. Crucial steps in the formation of ferroptosis include the accumulation of ferrous ions (Fe2+) and lipid peroxidation, of which are controlled by glutathione peroxidase 4 (GPX4). Its crucial role in stopping the spread of cancer has been shown by numerous studies undertaken in the last ten years. Epithelial-mesenchymal transition (EMT) is the process by which epithelial cells acquire mesenchymal characteristics. EMT is connected to carcinogenesis, invasiveness, metastasis, and therapeutic resistance in cancer. It is controlled by a range of internal and external signals and changes the phenotype from epithelial to mesenchymal like. Studies have shown that mesenchymal cancer cells tend to be more ferroptotic than their epithelial counterparts. Drug-resistant cancer cells are more easily killed by inducers of ferroptosis when they undergo EMT. Therefore, understanding the interaction between ferroptosis and EMT will help identify novel cancer treatment targets. In-depth discussion is given to the regulation of ferroptosis, the potential application of EMT in the treatment of cancer, and the relationships between ferroptosis, EMT, and signaling pathways associated with tumors. Invasion, metastasis, and inflammation in cancer all include ferroptosis and EMT. The goal of this review is to provide suggestions for future research and practical guidance for applying ferroptosis and EMT in clinical practice.

Clinical evaluation of oxaliplatin-loaded drug-eluting callispheres beads transarterial chemoembolization for unresectable or recurrent esophageal carcinoma.

BACKGROUND: A majority of esophageal carcinoma patients are diagnosed at an advanced stage and are no longer suitable for surgical resection. Drug-eluting beads transarterial chemoembolization (DEB-TACE) with oxaliplatin-loaded CalliSpheres beads (CB) have been used for advanced hepatocellular carcinoma and lung cancer, but they have not been reported for the treatment of unresectable or recurrent esophageal carcinoma. METHODS: DEB-TACE was performed on 22 patients with unresectable or recurrent esophageal carcinoma between March 2019 and May 2022. The clinical outcomes, complications, and efficacy were retrospectively recorded and analyzed. RESULTS: A total of 39 sessions of DEB-TACE were performed in 22 patients, with a technical success rate of 92.3% and clinical success rate of 65.0%. No severe complications such as procedure-related death, esophageal rupture or paraplegia were observed. Complete response, partial response, and stable disease were observed in 14.3% (2/14), 42.9% (6/14), and 21.4% (3/14) of patients 6 months after DEB-TACE, respectively. The objective response rates were 62.5%, 42.9% and 57.1% respectively at 1-, 3-, and 6-month after DEB-TACE. Subsequent interventional treatments were administered to 12 patients, including DEB-TACE for hepatic metastasis in 3 (13.6%), esophageal stenting in 5 (22.7%), and airway stent placement in 5 (22.7%). Two patients were lost to follow up. A total of 9 patients died due to tumor progression (n = 5), pneumatic infection (n = 1), and tumor-related massive esophageal hemorrhage (n = 3). The median overall survivals were 13.9 months and 26.5 months from the first session of DEB-TACE and the diagnosis of esophageal carcinoma, respectively. CONCLUSIONS: DEB-TACE with oxaliplatin-loaded CB is suggested as a safe and effective treatment of unresectable or recurrent esophageal carcinoma, and more studies are required to confirm its efficacy and safety.

Recent advances and applications of CRISPR-Cas9 in cancer immunotherapy.

The incidence and mortality of cancer are the major health issue worldwide. Apart from the treatments developed to date, the unsatisfactory therapeutic effects of cancers have not been addressed by broadening the toolbox. The advent of immunotherapy has ushered in a new era in the treatments of solid tumors, but remains limited and requires breaking adverse effects. Meanwhile, the development of advanced technologies can be further boosted by gene analysis and manipulation at the molecular level. The advent of cutting-edge genome editing technology, especially clustered regularly interspaced short palindromic repeats (CRISPR-Cas9), has demonstrated its potential to break the limits of immunotherapy in cancers. In this review, the mechanism of CRISPR-Cas9-mediated genome editing and a powerful CRISPR toolbox are introduced. Furthermore, we focus on reviewing the impact of CRISPR-induced double-strand breaks (DSBs) on cancer immunotherapy (knockout or knockin). Finally, we discuss the CRISPR-Cas9-based genome-wide screening for target identification, emphasis the potential of spatial CRISPR genomics, and present the comprehensive application and challenges in basic research, translational medicine and clinics of CRISPR-Cas9.

Multifaceted role of redox pattern in the tumor immune microenvironment regarding autophagy and apoptosis.

The reversible oxidation-reduction homeostasis mechanism functions as a specific signal transduction system, eliciting related physiological responses. Disruptions to redox homeostasis can have negative consequences, including the potential for cancer development and progression, which are closely linked to a series of redox processes, such as adjustment of reactive oxygen species (ROS) levels and species, changes in antioxidant capacity, and differential effects of ROS on downstream cell fate and immune capacity. The tumor microenvironment (TME) exhibits a complex interplay between immunity and regulatory cell death, especially autophagy and apoptosis, which is crucially regulated by ROS. The present study aims to investigate the mechanism by which multi-source ROS affects apoptosis, autophagy, and the anti-tumor immune response in the TME and the mutual crosstalk between these three processes. Given the intricate role of ROS in controlling cell fate and immunity, we will further examine the relationship between traditional cancer therapy and ROS. It is worth noting that we will discuss some potential ROS-related treatment options for further future studies.

Radiogenomics: a key component of precision cancer medicine.

Radiogenomics, focusing on the relationship between genomics and imaging phenotypes, has been widely applied to address tumour heterogeneity and predict immune responsiveness and progression. It is an inevitable consequence of current trends in precision medicine, as radiogenomics costs less than traditional genetic sequencing and provides access to whole-tumour information rather than limited biopsy specimens. By providing voxel-by-voxel genetic information, radiogenomics can allow tailored therapy targeting a complete, heterogeneous tumour or set of tumours. In addition to quantifying lesion characteristics, radiogenomics can also be used to distinguish benign from malignant entities, as well as patient characteristics, to better stratify patients according to disease risk, thereby enabling more precise imaging and screening. Here, we have characterised the radiogenomic application in precision medicine using a multi-omic approach. we outline the main applications of radiogenomics in diagnosis, treatment planning and evaluations in the field of oncology with the aim of developing quantitative and personalised medicine. Finally, we discuss the challenges in the field of radiogenomics and the scope and clinical applicability of these methods.

Machine learning algorithm-generated and multi-center validated melanoma prognostic signature with inspiration for treatment management.

BACKGROUND: Although immunotherapy and targeted treatments have dramatically improved the survival of melanoma patients, the intra- or intertumoral heterogeneity and drug resistance have hindered the further expansion of clinical benefits. METHODS: The 96 combination frames constructed by ten machine learning algorithms identified a prognostic consensus signature based on 1002 melanoma samples from nine independent cohorts. Clinical features and 26 published signatures were employed to compare the predictive performance of our model. RESULTS: A machine learning-based prognostic signature (MLPS) with the highest average C-index was developed via 96 algorithm combinations. The MLPS has a stable and excellent predictive performance for overall survival, superior to common clinical traits and 26 collected signatures. The low MLPS group with a better prognosis had significantly enriched immune-related pathways, tending to be an immune-hot phenotype and possessing potential immunotherapeutic responses to anti-PD-1, anti-CTLA-4, and MAGE-A3. On the contrary, the high MLPS group with more complex genomic alterations and poorer prognoses is more sensitive to the BRAF inhibitor dabrafenib, confirmed in patients with BRAF mutations. CONCLUSION: MLPS could independently and stably predict the prognosis of melanoma, considered a promising biomarker to identify patients suitable for immunotherapy and those with BRAF mutations who would benefit from dabrafenib.

Gastrointestinal symptoms of long COVID-19 related to the ectopic colonization of specific bacteria that move between the upper and lower alimentary tract and alterations in serum metabolites.

BACKGROUND: Since the coronavirus disease 2019 (COVID-19) outbreak, many COVID-19 variants have emerged, causing several waves of pandemics and many infections. Long COVID-19, or long-term sequelae after recovery from COVID-19, has aroused worldwide concern because it reduces patient quality of life after rehabilitation. We aimed to characterize the functional differential profile of the oral and gut microbiomes and serum metabolites in patients with gastrointestinal symptoms associated with long COVID-19. METHODS: We prospectively collected oral, fecal, and serum samples from 983 antibiotic-naïve patients with mild COVID-19 and performed a 3-month follow-up postdischarge. Forty-five fecal and saliva samples, and 25 paired serum samples were collected from patients with gastrointestinal symptoms of long COVID-19 at follow-up and from healthy controls, respectively. Eight fecal and saliva samples were collected without gastrointestinal symptoms of long COVID-19 at follow-up. Shotgun metagenomic sequencing of fecal samples and 2bRAD-M sequencing of saliva samples were performed on these paired samples. Two published COVID-19 gut microbiota cohorts were analyzed for comparison. Paired serum samples were analyzed using widely targeted metabolomics. RESULTS: Mild COVID-19 patients without gastrointestinal symptoms of long COVID-19 showed little difference in the gut and oral microbiota during hospitalization and at follow-up from healthy controls. The baseline and 3-month samples collected from patients with gastrointestinal symptoms associated with long COVID-19 showed significant differences, and ectopic colonization of the oral cavity by gut microbes including 27 common differentially abundant genera in the Proteobacteria phylum, was observed at the 3-month timepoint. Some of these bacteria, including Neisseria, Lautropia, and Agrobacterium, were highly related to differentially expressed serum metabolites with potential toxicity, such as 4-chlorophenylacetic acid, 5-sulfoxymethylfurfural, and estradiol valerate. CONCLUSIONS: Our study characterized the changes in and correlations between the oral and gut microbiomes and serum metabolites in patients with gastrointestinal symptoms associated with long COVID-19. Additionally, our findings reveal that ectopically colonized bacteria from the gut to the oral cavity could exist in long COVID-19 patients with gastrointestinal symptoms, with a strong correlation to some potential harmful metabolites in serum.

A retrospective pilot study of transarterial chemoembolisation using camrelizumab-eluting Callisphere beads for unresectable hepatocellular carcinoma.

BACKGROUND: Our objective was to assess the efficacy and safety of initial hepatic arterial infusion of chemotherapy combined with transarterial chemoembolisation using camrelizumab-eluting Callisphere beads (camrelizumab-DEB-TACE) for treating unresectable hepatocellular carcinoma (HCC). METHODS: Enrolment included patients with unresectable HCC who underwent camrelizumab-DEB-TACE treatment from September 2021 to February 2023. The assessment included the examination of tumour response, overall survival (OS), progression-free survival (PFS), and the monitoring of adverse events (AEs). RESULTS: Twenty-one patients were included in the study. The objective response rates (ORR) and disease control rates (DCR) were 55.0% and 90.0% at 1 month and 57.9% and 78.9% at 3 months, respectively. The median PFS and OS were 7.4 and 15.5 months months, respectively. Among the 21 patients, 4 underwent more than 2 procedures of camrelizumab-DEB-TACE, with a mean of 1.9 ± 1.1 procedures (range: 1-4) per patient. No severe complications or treatment-related mortalities were observed. In addition, no patient developed severe AEs related to camrelizumab, such as reactive cutaneous capillary endothelial proliferation, immune-related pneumonia, or immune-related myocarditis. Nineteen patients experienced at least one type of AEs related to DEB-TACE, with abdominal pain (n = 16, 76.2%) being the most prevalent AE. CONCLUSION: Camrelizumab-DEB-TACE demonstrated effectiveness and safety as a treatment for unresectable HCC, with no occurrence of severe camrelizumab-related AEs.

TACE sequential MWA guided by cone-beam computed tomography in the treatment of small hepatocellular carcinoma under the hepatic dome.

PURPOSE: An assessment is being conducted to determine the safety and effectiveness of using Cone-beam computed tomography (CBCT)-guided transcatheter arterial chemoembolization (TACE) and microwave ablation (MWA) sequentially to treat small hepatocellular carcinomas (HCCs) located in the hepatic dome. MATERIALS AND METHODS: Fifty-three patients with small HCCs in the hepatic dome who underwent TACE combined with simultaneous CBCT-guided MWA were studied. Inclusion criteria were a single HCCs ≤ 5.0 cm or a maximum of three. The safety and interventional-related complications were monitored, and local tumor progression (LTP), overall survival (OS), and prognostic factors for LTP/OS were evaluated. RESULTS: The procedures were successfully accomplished in all patients. According to Common Terminology Criteria for Adverse Events (CTCAE), adverse reactions and complications are mainly Grade 1 or 2 (mild symptoms, no or local/noninvasive intervention indicated). Liver and kidney function and alpha-fetoprotein (AFP) levels remained within a reasonable range after 4 weeks of treatment (both p < 0.001). The mean LTP was 44.406 months (95% CI: 39.429, 49.383) and the mean OS rate was 55.157 months (95% CI: 52.559, 57.754). The combination treatment achieved 1-, 3-, and 5-year LTP rates of 92.5%, 69.6%, and 34.5%, respectively; and 1-, 3-, and 5-year OS rates of 100.0%, 88.4%, and 70.2%, respectively. Results from both univariate and multivariate Cox regression analyses showed that the tumor diameter (< 3 cm) and the distance to the hepatic dome (≥ 5 mm, < 10 mm) had a significant impact on the patient's LTP and OS, and were related to better survival. CONCLUSION: CBCT-guided TACE combined with simultaneous MWA was a safe and successful treatment of HCCs located under the hepatic dome.