Dual specific phosphatase 4 suppresses ferroptosis and enhances sorafenib resistance in hepatocellular carcinoma.

AIMS: This investigation aims to elucidate the mechanism underlying sorafenib-induced ferroptosis in hepatocellular carcinoma (HCC). METHODS: The role of dual specificity phosphatase 4 (DUSP4) in sorafenib-treated HCC was investigated using comprehensive assessments both in vitro and in vivo, including Western blotting, qRT-PCR, cell viability assay, lipid reactive oxygen species (ROS) assay, immunohistochemistry, and xenograft tumor mouse model. Additionally, label-free quantitative proteomics was employed to identify potential proteins associated with DUSP4. RESULTS: Our study revealed that suppression of DUSP4 expression heightens the susceptibility of HCC cells to ferroptosis inducers, specifically sorafenib and erastin, in both in vitro and in vivo settings. Furthermore, we identified DUSP4-mediated regulation of key ferroptosis-related markers, such as ferritin light chain (FTL) and ferritin heavy chain 1 (FTH1). Notably, label-free quantitative proteomics unveiled the phosphorylation of threonine residue T148 on YTH Domain Containing 1 (YTHDC1) by DUSP4. Further investigations unraveled that YTHDC1, functioning as an mRNA nuclear export regulator, is a direct target of DUSP4, orchestrating the subcellular localization of FTL and FTH1 mRNAs. Significantly, our study highlights a strong correlation between elevated DUSP4 expression and sorafenib resistance in HCC. CONCLUSIONS: Our findings introduce DUSP4 as a negative regulator of sorafenib-induced ferroptosis. This discovery opens new avenues for the development of ferroptosis-based therapeutic strategies tailored for HCC treatment.

Endogenously Gated DNA Walking Machine for Prescreened MicroRNA Detection in Extracellular Vesicles.

Tumor-derived extracellular vesicle (T-EV) microRNAs have been investigated as promising biomarkers in clinical diagnosis as well as disease progression monitoring. However, the expression profiles of microRNA in different tissues vary widely, the precise monitoring of microRNA levels in EVs originating from diseased tissues is susceptible to background interference, thus remains a challenge. Conventional assays require extensive processing, such as EV isolation and even sample lysis, which is both slow and laborious, and the cumbersome pretreatment could spoil the downstream analysis. To address this issue, we developed a generalizable strategy for T-EVs-selective activation and therefore specific amplified microRNA imaging. The conditional signal amplification is established by integrating a traditional DNA walker system with endogenously activated motif to achieve sensitized microRNA imaging in T-EVs. The preorganized endogenous activation with additional sensing criteria narrowed the scope against the complex specimens, and the amplified sensing with reduced off-target signals was supposed to be sensitive to monitor the tiny changes of microRNA expression during the disease course, which holds great potential for accurate diagnosis and prognosis.

Avoiding the Kinetic Inertness of Chromium Ions Using a Coordination Substitution Strategy for the Rapid Synthesis of Chromium-Based Metal-Organic Frameworks.

Chromium-based metal-organic frameworks (Cr-MOFs) are very attractive in a wide range of applications due to their robustness and high porosity. However, the kinetic inertness of chromium ions results in the synthesis of Cr-MOFs often taking prolonged reaction times, which limit their industrial applications. Herein, we report a novel synthesis strategy based on coordination substitution, which overcomes the kinetic inertness of chromium ions and can synthesize Cr-MOFs in a shorter time. The versatility of this strategy has been demonstrated by producing several known Cr-MOFs, such as TYUT-96Cr, MIL-100Cr, MIL-101Cr, and MIL-53Cr. PXRD, SEM, TEM, 77 K N2 adsorption, and TGA have proved that the Cr-MOFs synthesized using this new strategy have good crystallinity, high porosity, and excellent thermal stability. The synthesis mechanism was investigated using theoretical calculations.

Change of indocyanine green clearance ability and liver function after transcatheter intra-arterial therapies and its impact on outcomes of resectable hepatocellular carcinoma: a retrospective cohort study.

BACKGROUND: Indocyanine green (ICG) clearance test is a classical measurement of hepatic reserve, which involves surgical safety and patient recovery of hepatocellular carcinoma (HCC). The authors aim to compare effects of hepatic arterial infusion chemotherapy (HAIC) and transcatheter arterial chemoembolization (TACE) on liver function and outcomes of subsequent hepatectomy. MATERIAL AND METHODS: HCC patients receiving HAIC/TACE in SYSUCC with repeated ICG clearance tests were retrospectively enrolled. ICG eliminating rate (ICG-K), ICG retention rate at 15 min (ICG-R15) and ordinary laboratory tests were collected. Peri-therapeutic changes of values were compared between the groups. Propensity score matching (PSM) and inverse probability of treatment weighing (IPTW) were employed to validate findings. Post-hepatectomy liver failure (PHLF), overall survival (OS) and recurrence-free survival (RFS) were analyzed in patients with subsequent curative hepatectomy. RESULTS: Two hundred and four patients treated with HAIC ( n =130) and TACE ( n =74) were included. ΔICG-R15 was greater in the HAIC arm before matching (mean, 3.8% vs. 0.7%, P <0.001), after PSM (mean, 4.7% vs. 1.1%, P =0.014) and IPTW (mean, 2.0% vs. -3.6%, P <0.001). No difference was found for ΔALB, ΔALBI, ΔTBIL, ΔALT, ΔAST and ΔPT-INR. Multivariable analyses revealed elder age, cirrhosis, HAIC, greater ΔTBIL and ΔALBI were associated with deteriorating ICG-R15. Among those (105 for HAIC and 48 for TACE) receiving hepatectomy, occurrence of grade B/C PHLF (4.8% vs. 8.3%, P =0.616), OS (median, unreached vs. unreached, P =0.94) and RFS (median, 26.7 vs. 17.1 months, P =0.096) were comparable between the two arms. In subgroup analyses, preoperative HAIC yield superior RFS (median, 26.7 vs. 16.2 months, P =0.042) in patients with baseline ICG-R15 less than or equal to 10%. CONCLUSION: Preoperative FOLFOX-HAIC caused apparent impairment of ICG clearance ability than TACE yet comparable impact on liver function and post-hepatectomy outcomes.

Size-Tunable Nanoregulator-Based Radiofrequency Ablation Suppresses MDSCs and Their Compensatory Immune Evasion in Hepatocellular Carcinoma.

Radiofrequency ablation (RFA) is a widely used therapy for hepatocellular carcinoma (HCC). However, in cases of insufficient RFA (iRFA), nonlethal temperatures in the transition zone increase the risk of postoperative relapse. The pathological analysis of HCC tissues shows that iRFA-induced upregulation of myeloid-derived suppressor cells (MDSCs) in residual tumors is critical for postoperative recurrence. Furthermore, this study demonstrates, for the first time, that combining MDSCs suppression strategy during iRFA can unexpectedly lead to a compensatory increase in PD-L1 expression on the residual MDSCs, attributed to relapse due to immune evasion. To address this issue, a novel size-tunable hybrid nano-microliposome is designed to co-deliver MDSCs inhibitors (IPI549) and αPDL1 antibodies (LPIP) for multipathway activation of immune responses. The LPIP is triggered to release immune regulators by the mild heat in the transition zone of iRFA, selectively inhibiting MDSCs and blocking the compensatory upregulation of PD-L1 on surviving MDSCs. The combined strategy of LPIP + iRFA effectively ablates the primary tumor by activating immune responses in the transition zone while suppressing the compensatory immune evasion of surviving MDSCs. This approach avoids the relapse of the residual tumor in a post-iRFA incomplete ablation model and appears to be a promising strategy in RFA for the eradication of HCC.

Inter-Group Face Recognition Bias Was Modulated by the Group Status.

Previous studies have shown that social categorization can induce an own-group face recognition bias. However, similar and better other-group face recognition emerged recently. In this research, we aimed to examine whether competitive cues and group status accompanied by social categorization can modulate the inter-group face recognition bias. Moreover, we investigated how the group identification of individuals with different statuses affected the inter-group face recognition bias. The results indicated that an own-group face recognition bias emerged for targets with in-group labels compared to out-group labels. Moreover, when the group labels signaled competitive cues, the own-group face recognition bias was reversed. Furthermore, low-status and similar-status individuals exhibited out-group face recognition bias, but high-status individuals did not. In addition, the higher the in-group identification scores of participants from the low-status group, the stronger the out-group face recognition bias. These results suggested that competitive cues would reverse the own-group face recognition bias and the group status would play a modulating role in face recognition bias.

Comparison of stereotactic body radiation therapy with hepatic resection and radiofrequency ablation as initial treatment in patients with early-stage hepatocellular carcinoma.

Background: Stereotactic body radiation therapy (SBRT) has emerged as a novel intervention for early-stage hepatocellular carcinoma (HCC). The outcomes of SBRT, liver resection (LR), and radiofrequency ablation (RFA) as the initial treatment for AJCC stage I HCC patients remain unclear. Methods: Patients with AJCC stage I HCC from the Surveillance, Epidemiology and End Results database were analyzed for survival rates using the Kaplan-Meier method and stratified according to tumor size: S subgroup (≤2 cm), M subgroup (>2-3 cm), and L subgroup (>3 cm). For factors including age, year of diagnosis, sex, race, grade, tumor size, AFP, and fibrosis score, propensity score matching was performed to eliminate the imbalance of baseline features and selection bias during groups. Results: A total of 4,002 patients were included; the difference in median overall survival (mOS) between the SBRT group and the LR or RFA group in the S subgroup was statistically insignificant (p=0.109 and p=0.744), while that of the RFA group was significantly worse than that of the LR group (p <0.001). In the M and L subgroups, the mOS of the SBRT group was worse than that of the RFA group (p=0.040 and p<0.001, respectively). The mOS of LR was the best when compared with either the SBRT or RFA group regardless of the subgroup M or L (all p<0.001). Conclusion: For HCC ≤ 2 cm, SBRT can be used as an alternative treatment for RFA. For patients with HCC larger than 2 cm, RFA can provide better long-term survival than SBRT, while LR remains the best choice.

Long noncoding RNA TINCR facilitates hepatocellular carcinoma progression and dampens chemosensitivity to oxaliplatin by regulating the miR-195-3p/ST6GAL1/NF-κB pathway.

BACKGROUND: Long non-coding RNAs (lncRNA) have an essential role in progression and chemoresistance of hepatocellular carcinoma (HCC). In-depth study of specific regulatory mechanisms is of great value in providing potential therapeutic targets. The present study aimed to explore the regulatory functions and mechanisms of lncRNA TINCR in HCC progression and oxaliplatin response. METHODS: The expression of TINCR in HCC tissues and cell lines was detected by quantitative reverse transcription PCR (qRT-PCR). Cell proliferation, migration, invasion, and chemosensitivity were evaluated by cell counting kit 8 (CCK8), colony formation, transwell, and apoptosis assays. Luciferase reporter assays and RNA pulldown were used to identify the interaction between TINCR and ST6 beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1) via miR-195-3p. The corresponding functions were verified in the complementation test and in vivo animal experiment. RESULTS: TINCR was upregulated in HCC and associated with poor patient prognosis. Silencing TINCR inhibited HCC proliferation, migration, invasion, and oxaliplatin resistance while overexpressing TINCR showed opposite above-mentioned functions. Mechanistically, TINCR acted as a competing endogenous (ceRNA) to sponge miR-195-3p, relieving its repression on ST6GAL1, and activated nuclear factor kappa B (NF-κB) signaling. The mouse xenograft experiment further verified that knockdown TINCR attenuated tumor progression and oxaliplatin resistance in vivo. CONCLUSIONS: Our finding indicated that there existed a TINCR/miR-195-3p/ST6GAL1/NF-κB signaling regulatory axis that regulated tumor progression and oxaliplatin resistance, which might be exploited for anticancer therapy in HCC.

PIM2 Expression Induced by Proinflammatory Macrophages Suppresses Immunotherapy Efficacy in Hepatocellular Carcinoma.

Cancer immunotherapy restores or enhances the effector function of T cells in the tumor microenvironment, but the efficacy of immunotherapy has been hindered by therapeutic resistance. Here, we identify the proto-oncogene serine/threonine protein kinase PIM2 as a novel negative feedback regulator of IFNγ-elicited tumor inflammation, thus endowing cancer cells with aggressive features. Mechanistically, IL1ß derived from IFNγ-polarized tumor macrophages triggered PIM2 expression in cancer cells via the p38 MAPK/Erk and NF-κB signaling pathways. PIM2+ cancer cells generated by proinflammatory macrophages acquired the capability to survive, metastasize, and resist T-cell cytotoxicity and immunotherapy. A therapeutic strategy combining immune checkpoint blockade (ICB) with IL1ß blockade or PIM2 kinase inhibition in vivo effectively and successfully elicited tumor regression. These results provide insight into the regulatory and functional features of PIM2+ tumors and suggest that strategies to influence the functional activities of inflammatory cells or PIM2 kinase may improve the efficacy of immunotherapy. SIGNIFICANCE: Cross-talk between T cells and macrophages regulates cancer cell PIM2 expression to promote cancer aggressiveness, revealing translational approaches to improve response to ICB in hepatocellular carcinoma.

Optimal subsequent treatments for patients with hepatocellular carcinoma resistant to anti-PD-1 treatment.

Aim: The subsequent treatments for patients with hepatocellular carcinoma (HCC) resistant to immunotherapy remain unclear. This study aimed to identify optimal treatments for HCC patients with progression after anti-PD-1 therapy. Methods: The authors retrospectively analyzed 197 HCC patients with progressive disease after anti-PD-1 treatment. These patients were classified into initial resistant and secondary resistant groups. Results: In the initial resistant group, subsequent treatment with PD-1 antibody plus locoregional therapy prolonged post-progression survival and overall survival (p = 0.025 and 0.029, respectively). In the secondary resistant group, subsequent treatment did not improve the prognosis of patients. Conclusion: Subsequent PD-1 antibody plus locoregional therapy could achieve survival benefits in HCC patients initially resistant to anti-PD-1 immunotherapy.

Lay abstract This study explored the optimal subsequent treatments for patients with hepatocellular carcinoma resistant to anti-PD-1 therapy. Patients were classified into initial resistant and secondary resistant groups according to whether they had responses to previous anti-PD-1 immunotherapy. By evaluating the prognosis of different treatment modalities in the initial and secondary resistant groups, the authors found that subsequent PD-1 antibody plus locoregional therapy provided survival benefits for patients with hepatocellular carcinoma initially resistant to anti-PD-1 immunotherapy. As for patients with secondary resistance, the optimal subsequent treatments need to be further explored.

Hepatic Arterial Infusion Chemotherapy Combined With PD-1 Inhibitors Plus Lenvatinib Versus PD-1 Inhibitors Plus Lenvatinib for Advanced Hepatocellular Carcinoma.

BACKGROUND: Lenvatinib combined with programmed cell death protein-1 (PD-1) inhibitors has resulted in good survival outcomes in the treatment of unresectable hepatocellular carcinoma (HCC). Hepatic artery infusion chemotherapy (HAIC) has also attracted attention due to its high response rates and favorable survival for advanced HCC patients. The present study aimed to compare the efficacy of HAIC combined with PD-1 inhibitors plus lenvatinib (HPL) and PD-1 inhibitors plus lenvatinib (PL) in patients with advanced HCC. METHODS: Between July 2018 and December 2019, patients diagnosed with advanced HCC who initially received HPL or PL treatment were reviewed for eligibility. Efficacy was evaluated according to tumor response and survival. RESULTS: In total, 70 patients met the criteria and were included in the present study, and they were divided into the HPL group (n = 45) and PL group (n = 25). The overall response rate (40.0 vs. 16.0%, respectively; p = 0.038) and disease control rate (77.6 vs. 44.0%, respectively; p < 0.001) were higher in the HPL group than in the PL group. The median overall survival was 15.9 months in the HPL group and 8.6 months in the PL group (p = 0.0015; HR = 0.6; 95% CI 0.43-0.83). The median progression-free survival was 8.8 months in the HPL group and 5.4 months in the PL group (p = 0.0320; HR = 0.74; 95% CI 0.55-0.98). CONCLUSION: Compared to PL, HPL was associated with a significantly better treatment response and survival benefits for patients with advanced HCC.

A slowly-growing solitary skip lymph nodule of occult gastric cancer above the neck of pancreas: a case report.

BACKGROUND: Skip lymphatic metastasis (SK) is an exceptional and characteristic pattern of lymph node metastasis in gastric cancer (GC) with infrequent incidence. This is an extremely rare report of occult gastric cancer with solitary skip lymphatic metastasis as the initial and primary observation. CASE PRESENTATION: A 61-year-old woman, who complained of epigastric discomfort for several years, presented a solitary nodule upon pancreas neck examination by CT without performance on the primary lesion, even gastroscopy. During the preoperative 4-month follow-up, the nodule stayed stable without any therapy. The postoperative pathological examination confirmed the consistent diagnosis of gastric adenocarcinoma between the nodule and the stomach lesion, which was found by preoperative random biopsy of the mucosa. CONCLUSIONS: This case highlights the concentration on vigilance to the SK of GC and a closer observation for intra-abdominal nodules, even radiological suspicion of a benign lesion.