Development and experimental validation of a machine learning-based disulfidptosis-related ferroptosis score for hepatocellular carcinoma.

Disulfidoptosis and ferroptosis are two distinct programmed cell death pathways that have garnered considerable attention due to their potential as therapeutic targets. However, despite their significance of these pathways, the role of disulfidoptosis-related ferroptosis genes in hepatocellular carcinoma (HCC) remains unclear. In this study, we employed a comprehensive approach that utilized various sophisticated techniques such as Pearson analysis, differential analysis, uniCox regression, lasso, ranger, and multivariable Cox regression to develop the disulfidoptosis-related ferroptosis (DRF) score. We then classified patients with HCC into high- and low-score groups to examine the association between the DRF score and various outcomes, including prognosis, functional enrichment, immune infiltration, immunotherapy, TACE sensitivity, drug sensitivity, and single-cell level function. Finally, we conducted in vitro experiments to validate the function of KIF20A. Our analysis revealed that KIF20A, G6PD, SLC7A11, and SLC2A1 were integral to constructing the DRF score. Our findings showed that patients with low DRF scores had significantly better prognoses and were more responsive to immunotherapy, TACE, and chemotherapy than those with high DRF scores. Based on our results obtained from bulk RNA-seq, single-cell RNA-seq, and in vitro experiments, we identified the cell cycle pathway as the primary distinguished factor between high-score and low-score groups. This study sheds light on the contribution of disulfidoptosis-related ferroptosis genes to the development and progression of HCC. The information gleaned from this study can be leveraged to improve our understanding of their potential as therapeutic targets for HCC treatment.

Regulation of blue infertile flower pigmentation by WD40 transcription factor HmWDR68 in Hydrangea macrophylla 'forever summer'.

BACKGROUND: WD40 transcription factors are crucial in plant growth and developmental, significantly impacting plant growth regulation. This study investigates the WD40 transcription factor HmWDR68's role in developing the distinctive blue infertile flower colors in Hydrangea macrophylla 'Forever Summer'. METHODS AND RESULTS: The HmWDR68 gene was isolated by PCR, revealing an open reading frame of 1026 base pairs, which encodes 341 amino acids. Characterized by four WD40 motifs, HmWDR68 is a member of the WD40 family. Phylogenetic analysis indicates that HmWDR68 shares high homology with PsWD40 in Camellia sinensis and CsWD40 in Paeonia suffruticosa, both of which are integral in anthocyanin synthesis regulation. Quantitative real-time PCR (qRT-PCR) analysis demonstrated that HmWDR68 expression in the blue infertile flowers of 'Forever Summer' hydrangea was significantly higher compared to other tissues and organs. Additionally, in various hydrangea varieties with differently colored infertile flowers, HmWDR68 expression was markedly elevated in comparison to other hydrangea varieties, correlating with the development of blue infertile flowers. Pearson correlation analysis revealed a significant association between HmWDR68 expression and the concentration of delphinidin 3-O-glucoside, as well as key genes involved in anthocyanin biosynthesis (HmF3H, HmC3'5'H, HmDFR, and HmANS) in the blue infertile flowers of 'Forever Summer' hydrangea (P < 0.01). CONCLUSION: These findings suggest HmWDR68 may specifically regulate blue infertile flower formation in hydrangea by enhancing delphinidin-3-O-glucoside synthesis, modulating expression of HmF3H, HmC3'5'H, HmDFR and HmANS. This study provides insights into HmWDR68's role in hydrangea's blue flowers development, offering a foundation for further research in this field.

An integrative analysis reveals the prognostic value and potential functions of PSMD11 in hepatocellular carcinoma.

The global burden of hepatocellular carcinoma (HCC) as a preeminent etiology of cancer-related mortalities sheds light on the imperative necessity for a more profound comprehension of its fundamental biological mechanisms. In this context, the precise function of the 26S proteasome non-ATPase regulatory subunit 11 (PSMD11) in HCC remains equivocal. To address this vital knowledge gap, we interrogated the cancer genome atlas, genotype-tissue expression, International cancer genome consortium, gene expression omnibus, the cancer cell line encyclopedia, and tumor immune single-cell hub databases to evaluate the expression pattern of PSMD11, further confirmed by reverse-transcription quantitative polymerase chain reaction (RT-qPCR) in LO2, MHCC-97H, HepG2, and SMMC7721 cell lines. Additionally, we meticulously assessed the clinical significance and prognostic value of PSMD11, while also exploring its potential molecular mechanisms in HCC. Our findings demonstrated that PSMD11 was highly expressed in HCC tissues, correlating with pathologic stage and histologic grade, thereby conferring a poor prognosis. Mechanistically, PSMD11 appears to exert its tumorigenic effects through the modulation of tumor metabolism-related pathways. Impressively, low PSMD11 expression was associated with increased immune effector cell infiltration, heightened responsiveness to molecular targeted drugs such as dasatinib, erlotinib, gefitinib, and imatinib, as well as reduced somatic mutation rate. Additionally, we demonstrated that PSMD11 might modulate HCC development through intricate interactions with cuproptosis-related genes ATP7A, DLAT, and PDHA1. Our comprehensive analyses collectively suggest that PSMD11 represents a promising therapeutic target in HCC.

Long-term outcomes of combined transarterial chemoembolization and radiofrequency ablation versus RFA monotherapy for single hepatocellular carcinoma ≤3 cm: emphasis on local tumor progression.

PURPOSE: To compare the long-term outcomes of combined transarterial chemoembolization and radiofrequency ablation (TACE-RFA) with radiofrequency ablation (RFA) monotherapy for small (≤3 cm) hepatocellular carcinomas (HCCs). METHODS: A total of 248 patients with 329 HCC nodules who underwent TACE-RFA or RFA monotherapy as the only first-line treatment between January 2009 and December 2020 were included in this study. The technical success, complications, survival rate, and local tumor progression (LTP) rate were compared between the two treatments. RESULTS: The 1-, 3- and 5-year survival rates were similar between the two groups (98.7%, 93.0% and 75.9% vs 97.4%, 88.0% and 77.4%; p = 0.444). The 1-, 3-, and 5-year cumulative LTP rates were significantly lower in the TACE-RFA group than in the RFA monotherapy group (2.9%, 9.2%, and 13.8% vs. 5.2%, 17.0%, and 21.0%; p = 0.043). Subgroup analyses suggested that TACE-RFA showed significantly lower LTP rates than RFA monotherapy for small HCC with tumor size>2cm (p = 0.008), subphrenic location (p = 0.021), and perivessel (p = 0.030). Furthermore, HCC with well-defined lipiodol deposition in the TACE-RFA group showed better local tumor control than the small HCC in the RFA monotherapy group (p = 0.013). There was no significant difference in the technical success rates (p = 0.064) and complication rates (p = 0.952) between the two groups. CONCLUSIONS: TACE-RFA is superior to RFA monotherapy in providing local tumor control for small HCC with tumor size 2-3 cm in diameter, subphrenic location, perivessel and HCCs with well-defined lipiodol deposition by TACE before RFA.

Safety and Efficacy of Stent Graft Implantation for Malignant Superior Vena Cava Syndrome.

BACKGROUND: Patients with malignant superior vena cava syndrome (SVCS) usually require urgent treatments due to a high potential risk of early mortality. Stent implantation can rapidly improve the symptoms of SVCS, which may be beneficial to subsequent anti-tumor therapy. The aim of the study was to evaluate the clinical outcomes of stent graft implantation for the treatment of superior vena cava (SVC) obstruction caused by non-small cell lung carcinoma (NSCLC) with acute post-stenting occlusion. METHODS: Between October 2014 and December 2019, 16 patients were selected for stent graft implantation. Technical success and clinical efficacy were assessed. Stent patency and patient survival rates, as well as the complications were analyzed. RESULTS: There were 17 stent grafts implanted in 16 patients. The technical success was 100%. The residual stenosis after initial implantation was 64.0 ± 9.0%. The stent expanded to an optimal size in 5.5 ± 2.2 days after the initial deployment. Migration occurred when deploying of the stent graft in one patient; this stent graft was successfully stabilized by a second one. No other complications related to the procedure were found except one migration. At 1, 3, 6, 9 and 12 months, the cumulative survival rates were 100%, 75%, 56%, 19% and 0%, respectively. The mean OS was 173 days. The median survival was 166 days. CONCLUSIONS: Stent graft can be safely used in patients with SVC obstruction with a good long-term patency rate.

Radiofrequency ablation with or without transarterial chemoembolization for hepatocellular carcinoma meeting Milan criteria: a focus on tumor progression and recurrence patterns.

Background/objective: The aim of this study was to evaluate tumor progression and recurrence patterns of radiofrequency ablation (RFA) with or without transarterial chemoembolization (TACE) for treating hepatocellular carcinoma (HCC) that meets Milan criteria. Methods: This retrospective study included consecutive HCC patients meeting Milan criteria who underwent percutaneous RFA with or without TACE as initial treatment at a tertiary academic center between December 2017 and 2022. Technical success rate, local recurrence-free survival (LRFS), progression-free survival (PFS) and recurrence patterns were recorded. Results: A total of 135 HCC patients (109 male [80.7%]) with a mean age of 62 years and 147 target lesions were retrospectively enrolled. The technical success rate was 99.3%. The median LRFS was 60 months, and the cumulative 1-, 3-, and 5-year LRFS were 88.9%, 70.1%, and 30.0%, respectively. Additionally, the median PFS was 23 months, with cumulative 1-, 3-, and 5-year PFS of 74%, 30%, and 0%, respectively. Multivariate analysis confirmed that age > 60, alpha-fetoprotein (AFP) (> 10), and albumin were associated with PFS (2.34, p = 0.004; 1.96, p = 0.021; 0.94, p = 0.007, respectively). Six recurrence patterns were identified: local tumor progression (LTP) alone (n = 15, 25.0%), intrahepatic distant recurrence (IDR) alone (n = 34, 56.7%), extrahepatic recurrence (ER) alone (n = 2, 3.3%), IDR + ER (n = 2, 3.3%), LTP + IDR (n = 5, 8.8%), and LTP + IDR + ER (n = 2, 3.3%). IDR occurred most frequently as a sign of good local treatment. Conclusions: RFA in combination with TACE does not appear to provide an advantage over RFA alone in improving tumor progression in patients with HCC meeting the Milan criteria. However, further prospective studies are needed to confirm these findings and to determine the optimal treatment approach for this patient population.

Hormonal Regulation and Transcriptomic Insights into Flower Development in Hydrangea paniculata 'Vanilla Strawberry'.

Understanding the molecular mechanisms that regulate flower growth, development, and opening is of paramount importance, yet these processes remain less explored at the genetic level. Flower development in Hydrangea paniculata 'Vanilla Strawberry' is finely tuned through hormonal signals, yet the genetic underpinnings are not well defined. This study addresses the gap by examining the influence of gibberellic acid (GA3), salicylic acid (SA), and ethylene (ETH) on the flowering traits and underlying molecular responses. Treatment with 100 mg/L SA significantly improved chlorophyll content and bolstered the accumulation of soluble sugars and proteins, advancing the flowering onset by 6 days and lengthening the flowering period by 11 days. Concurrently, this treatment enhanced inflorescence dimensions, increasing length, width, and petal area by 22.76%, 26.74%, and 27.45%, respectively. Contrastingly, 100 mg/L GA3 expanded inflorescence size but postponed flowering initiation and decreased inflorescence count. Higher concentrations of SA and GA3, as well as any concentration of ETH, resulted in delayed flowering and inferior inflorescence attributes. A physiological analysis over 50 days revealed that these regulators variably affected sugar and protein levels and modified antioxidant enzyme activities. An RNA-seq analysis during floral development highlighted significant transcriptomic reprogramming, with SA treatment downregulating Myb transcription factors, implicating them in the modulation of flowering timing and stress adaptation. These findings illuminate the complex interplay between hormonal treatments, gene expression, and flowering phenotypes in Hydrangea paniculata, offering valuable perspectives for ornamental horticulture optimization.

Systemic Inflammation-Based Staging System for Hepatocellular Carcinoma After Drug-Eluting Beads Transarterial Chemoembolization: A Multicenter Study.

RATIONALE AND OBJECTIVES: The optimal prognostic assessment for patients with hepatocellular carcinoma (HCC) after drug-eluting bead transarterial chemoembolization (DEB-TACE) remains unclear. This study aimed to propose a novel staging system in comparison with the current staging systems for HCC following DEB-TACE. MATERIALS AND METHODS: From four centers, patients with HCC undergoing DEB-TACE as the initial therapy were retrospectively included and classified into training and validation sets. Multivariable regression was used to determine the independent prognostic factors in the training set. A novel staging system incorporating the independent factors was proposed and externally validated in terms of discrimination and calibration compared to other staging systems in both sets. RESULTS: The training and validation sets included 335 and 99 patients, respectively. Multivariable regression revealed independent factors including alpha-fetoprotein level, aspartate aminotransferase to lymphocyte count ratio index, maximum tumor diameter, Child-Pugh class, and portal vein invasion. The novel prognostic staging system, named PADCA, was proposed and outperformed other staging systems with the highest C-index, area under the curve, Wald test value, clinical benefit, and the lowest Akaike information criterion in the training and validation sets. CONCLUSION: The PADCA staging system has a superior prognostic predictive ability compared to the current staging systems. PADCA can assist clinicians in screening out the patients most likely to derive benefit from DEB-TACE and guiding the formulation of therapy and follow-up strategy.

Lipiodol combined with drug-eluting beads versus drug-eluting beads alone for transarterial chemoembolization of hepatocellular carcinoma: a multicenter study.

RATIONALE AND OBJECTIVES: This study aimed to propose a novel approach of lipiodol combined with drug-eluting beads transarterial chemoembolization (Lipiodol-DEB TACE) and to compare the safety and efficacy with DEB-TACE alone for patients with unresectable hepatocellular carcinoma (HCC). MATERIALS AND METHODS: From the database of four centers, the records of patients with HCC who received DEB-TACE or Lipiodol-DEB TACE as initial treatment were retrospectively evaluated. The tumor response was measured based on the Modified Response Evaluation Criteria in Solid Tumors. Overall survival (OS), progression-free survival (PFS) and adverse events (AEs) were compared between two groups. RESULTS: A total of 244 patients were included with 160 patients receiving DEB-TACE and 84 patients receiving Lipiodol-DEB TACE. Lipiodol-DEB TACE group had higher objective response rate (86.9 % vs. 76.3 %), higher disease control rate (97.6 % vs. 88.8 %), longer median OS (42.6 vs. 25.8 months) and longer median PFS (34.0 vs. 17.0 months) than DEB-TACE group (P < 0.05). There was no significant difference observed in the incidence of AEs between two groups. Cox analysis identified total bilirubin level, maximum tumor diameter, TACE method and portal vein invasion as independent prognostic factors. CONCLUSION: Lipiodol-DEB TACE was a safe option and associated with improved tumor response and survival outcome compared to DEB-TACE alone for selected patients with HCC.

Loadability and Releasing Profiles In Vitro and Pharmacokinetics In Vivo of Vinorelbine and Raltitrexed by CalliSpheres Beads.

Background: This study investigated the loadability and releasing profiles of vinorelbine and raltitrexed from CalliSpheres® Beads (CB) in vitro, and further explored the pharmacokinetic features of vinorelbine and raltitrexed eluting CB in vivo. Materials and Methods: Ten milligrams vinorelbine and 0.2 mg raltitrexed were mixed with 0.15 g CB at two sizes (100-300 and 300-500 µm) for 24 h, respectively, to measure the loadability. Then vinorelbine/raltitrexed loading CBs were placed in 20% phosphate-buffered saline for 24 h to measure the release profiles. Transcatheter arterial chemoembolization (TACE) with 1 mg vinorelbine eluting CBs (two sizes respectively) and transcatheter arterial hepatic infusion (TAI) with 1 mg vinorelbine were performed in 9 rabbits (3 rabbits in each group). The above experiments were repeated with 0.2 mg raltitrexed. Results: Vinorelbine loading efficiency quickly reached 90% within 10 min with maximum loadability >90% by CB with both two sizes, and vinorelbine release rate gradually increased to ∼100% within 1 h. Raltitrexed loading efficiency gradually increased to >40% within 15 min, then slowly increased to >60% within 24 h, with maximum loadability <70% by CB with both sizes, and raltitrexed release rate gradually increased to >90% within 1 h. Besides, vinorelbine/raltitrexed eluting CB showed greatly decreased maximum serum concentration (Cmax) of the drug compared with TAI in rabbits with similar area under the curve (0-t), mean residence time (0-t), and half-time (T1/2). Conclusion: CB exhibits good loadability and an acceptable releasing profile for eluting vinorelbine and raltitrexed, and shows lower Cmax and numerically stable concentration than TAI.

Long-term outcome of percutaneous radiofrequency ablation for periportal hepatocellular carcinoma: tumor recurrence or progression, survival and clinical significance.

BACKGROUND/AIM: Recent studies have suggested that periportal location of percutaneous radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) is considered as one of the independent risk factors for local tumor progression (LTP). However, the long-term therapeutic outcomes of percutaneous RFA as the first-line therapy for single periportal HCCand corresponding impacts on tumor recurrence or progression are still unclear. MATERIALS AND METHODS: From February 2011 to October 2020, a total of 233 patients with single nodular HCC ≤ 5 cm who underwent RFA ± transarterial chemoembolization (TACE) as first-line therapy was enrolled and analyzed, including 56 patients in the periportal group and 177 patients in the nonperiportal group. The long-term therapeutic outcomes between the two groups were compared, risk factors of tumor recurrence or progression were evaluated. RESULTS: The LTP rates at 1, 3, and 5 years were significantly higher in the periportal group than those in the nonperiportal group (15.7, 33.7, and 46.9% vs 6.0, 15.7, and 28.7%, respectively, P = 0.0067). The 1-, 3- and 5-year overall survival (OS) rates in the periportal group were significantly worse than those in the nonperiportal group (81.3, 65.1 and 42.9% vs 99.3, 90.4 and 78.1%, respectively, P<0.0001). In the subgroup of single HCC ≤ 3 cm, patients with periportal HCC showed significantly worse LTP P = 0.0006) and OS (P<0.0001) after RFA than patients with single nonperiportal HCC; The univariate and multivariate analyses revealed that tumor size, periportal HCC and AFP ≥ 400ug/ml were independent prognostic factors for tumor progression after RFA. Furthermore, patients with single periportal HCC had significantly higher risk for IDR(P = 0.0012), PVTT(P<0.0001) and extrahepatic recurrence(P = 0.0010) after RFA than those patients with single nonperiportal HCC. . CONCLUSION: The long-term therapeutic outcomes of RFA as the first-line therapy for single periportal HCC were worse than those for single nonperiportal HCC, an increased higher risk of tumor recurrence or progression after RFA was significantly associated with periportal HCC.