Protein tyrosine phosphatase non-receptor II: A possible biomarker of poor prognosis and mediator of immune evasion in hepatocellular carcinoma.

BACKGROUND: The incidence of primary liver cancer is increasing year by year. In 2022 alone, more than 900000 people were diagnosed with liver cancer worldwide, with hepatocellular carcinoma (HCC) accounting for 75%-85% of cases. HCC is the most common primary liver cancer. China has the highest incidence and mortality rate of HCC in the world, and it is one of the malignant tumors that seriously threaten the health of Chinese people. The onset of liver cancer is occult, the early cases lack typical clinical symptoms, and most of the patients are already in the middle and late stage when diagnosed. Therefore, it is very important to find new markers for the early detection and diagnosis of liver cancer, improve the therapeutic effect, and improve the prognosis of patients. Protein tyrosine phosphatase non-receptor 2 (PTPN2) has been shown to be associated with colorectal cancer, triple-negative breast cancer, non-small cell lung cancer, and prostate cancer, but its biological role and function in tumors remain to be further studied. AIM: To combine the results of relevant data obtained from The Cancer Genome Atlas (TCGA) to provide the first in-depth analysis of the biological role of PTPN2 in HCC. METHODS: The expression of PTPN2 in HCC was first analyzed based on the TCGA database, and the findings were then verified by immunohistochemical staining, quantitative real-time polymerase chain reaction (qRT-PCR), and immunoblotting. The value of PTPN2 in predicting the survival of patients with HCC was assessed by analyzing the relationship between PTPN2 expression in HCC tissues and clinicopathological features. Finally, the potential of PTPN2 affecting immune escape of liver cancer was evaluated by tumor immune dysfunction and exclusion and immunohistochemical staining. RESULTS: The results of immunohistochemical staining, qRT-PCR, and immunoblotting in combination with TCGA database analysis showed that PTPN2 was highly expressed and associated with a poor prognosis in HCC patients. Kyoto Encyclopedia of Genes and Genomes enrichment analysis showed that PTPN2 was associated with various pathways, including cancer-related pathways, the Notch signaling pathway, and the MAPK signaling pathway. Gene Set Enrichment Analysis showed that PTPN2 was highly expressed in various immune-related pathways, such as the epithelial mesenchymal transition process. A risk model score based on PTPN2 showed that immune escape was significantly enhanced in the high-risk group compared with the low-risk group. CONCLUSION: This study investigated PTPN2 from multiple biological perspectives, revealing that PTPN2 can function as a biomarker of poor prognosis and mediate immune evasion in HCC.

Liver transplantation following two conversions in a patient with huge hepatocellular carcinoma and portal vein invasion: A case report.

BACKGROUND: Surgical resection and liver transplantation (LT) are the most effective curative options for hepatocellular carcinoma (HCC). However, few patients with huge HCC (> 10 cm in diameter), especially those with portal vein tumor thrombus (PVTT), can receive these treatments. Selective internal radiation therapy (SIRT) can be used as a conversion therapy for them because it has the dual benefit of shrinking tumors and increasing residual hepatic volume. However, in patients with huge HCC, high lung absorbed dose often prevents them from receiving SIRT. CASE SUMMARY: A 35-year-old man was admitted because of emaciation and pain in the hepatic region for about 1 month. The computed tomography scan showed a 20.2 cm × 19.8 cm tumor located in the right lobe-left medial lobes with right portal vein and right hepatic vein invasion. After the pathological type of HCC was confirmed by biopsy, two conversions were presented. The first one was drug-eluting bead transarterial chemoembolization plus hepatic arterial infusion chemotherapy and lenvatinib and sintilimab, converted to SIRT, and the second one was sequential SIRT with continued systemic treatment. The tumor size significantly decreased from 20.2 cm × 19.8 cm to 16.2 cm × 13.8 cm, then sequentially to 7.8 cm × 6.8 cm. In the meantime, the ratio of spared volume to total liver volume increased gradually from 34.4% to 55.7%, then to 62.9%. Furthermore, there was visualization of the portal vein, indicating regression of the tumor thrombus. Finally, owing to the new tumor in the left lateral lobe, the patient underwent LT instead of resection without major complications. CONCLUSION: Patients with inoperable huge HCC with PVTT could be converted to SIRT first and accept surgery sequentially.

Dronedarone hydrochloride (DH) induces pancreatic cancer cell death by triggering mtDNA-mediated pyroptosis.

Pancreatic cancer is one of the leading causes of cancer-associated mortality, with a poor treatment approach. Previous study has shown that inducing pyroptosis in pancreatic ductal adenocarcinoma (PDAC) slows the growth of PDACs, implying that pyroptosis inducers are potentially effective for PDAC therapy. Here, we found that Dronedarone hydrochloride (DH), an antiarrhythmic drug, induces pyroptosis in pancreatic cancer cells and inhibits PDAC development in mice. In PANC-1 cells, DH caused cell death in a dosage- and time-dependent manner, with only pyroptosis inhibitors and GSDMD silencing rescuing the cell death, indicating that DH triggered GSDMD-dependent pyroptosis. Further work revealed that DH increased mitochondrial stresses and caused mitochondrial DNA (mtDNA) leakage, activating the cytosolic STING-cGAS and pyroptosis pathways. Finally, we assessed the anti-cancer effects of DH in a pancreatic cancer mouse model and found that DH treatment suppressed pancreatic tumor development in vivo. Collectively, our investigation demonstrates that DH triggers pyroptosis in PDAC and proposes its potential effects on anti-PDAC growth.

Parthenolide Inhibits Synthesis and Promotes Degradation of Programmed Cell Death Ligand 1 and Enhances T Cell Tumor-Killing Activity.

Parthenolide is a germacrane sesquiterpene lactone separated from the traditional medicinal plant feverfew. Previous studies have shown that parthenolide possesses many pharmacological activities, involving anti-inflammatory and anticancer activities. However, the antitumor mechanism of parthenolide has not been fully elucidated. Thus, we investigate the potential antitumor mechanisms of parthenolactone. We predicted through network pharmacology that parthenolide may target HIF-1α to interfere with the occurrence and development of cancer. We found that parthenolide inhibited PD-L1 protein synthesis through mTOR/p70S6K/4EBP1/eIF4E and RAS/RAF/MEK/MAPK signaling pathways and promoted PD-L1 protein degradation through the lysosomal pathway, thereby inhibiting PD-L1 expression. Immunoprecipitation and Western blotting results demonstrated that parthenolide inhibited PD-L1 expression by suppressing HIF-1α and RAS cooperatively. We further proved that parthenolide inhibited cell proliferation, migration, invasion, and tube formation via down-regulating PD-L1. Moreover, parthenolide increased the effect of T cells to kill tumor cells. In vivo xenograft assays further demonstrated that parthenolide suppressed the growth of tumor xenografts. Collectively, we report for the first time that parthenolide enhanced T cell tumor-killing activity and suppressed cell proliferation, migration, invasion, and tube formation by PD-L1. The current study provides new insight for the development of parthenolide as a novel anticancer drug targeting PD-L1.

Association between perioperative hemoglobin decrease and outcomes of transfusion in patients undergoing on-pump cardiac surgery: An observational study from two Chinese heart centers.

Background: It is unclear how perioperative hemoglobin decrease (ΔHb) influences the balance between risks and benefits of red blood cell transfusion after cardiac surgery. Methods: We retrospectively analyzed data on 8186 adults who underwent valve surgery and/or coronary artery bypass grafting under cardiopulmonary bypass at two large cardiology centers. We explored the potential association of ΔHb, defined relative to the preoperative level and postoperative nadir, with a composite outcome of in-hospital mortality, myocardial infarction, stroke, and acute kidney injury using multivariable logistic regression, restricted cubic spline, and piecewise-linear models. Results: Among 6316 patients without preoperative anemia, ΔHb ≥ 50 % was associated with an elevated risk of the composite outcome [adjusted odds ratio (aOR) 1.95, 95 % confidence interval (CI) 1.81-2.35]. Among 869 patients without preoperative anemia and with ΔHb ≥ 50 %, postoperative transfusion of no more than four units of red blood cell appeared to decrease the risk of the composite outcome, whereas transfusion of more than six units increased risk. Among 5447 patients without preoperative anemia and with ΔHb < 50 %, postoperative transfusion appeared not to decrease the risk of the composite outcome. Among 1870 patients with preoperative anemia, ΔHb ≥ 30 % significantly increased the risk of the composite outcome (aOR 1.61, 95 % CI 1.23-2.10), and this risk might be moderated by postoperative transfusion of no more than four units of red blood cell, but increased by transfusion of more than six units. Conclusions: ΔHb may influence the balance between risks and benefits of red blood cell transfusion after cardiac surgery.

Comparison of virtual and true non-contrast images from dual-layer spectral detector computed tomography (CT) in patients with colorectal cancer.

Background: Colorectal cancer (CRC) is commonly assessed by computed tomography (CT), but the associated radiation exposure is a major concern. This study aimed to quantitatively and qualitatively compare the image quality of virtual non-contrast (VNC) images reconstructed from arterial and portal venous phases with that of true non-contrast (TNC) images in patients with CRC to assess the potential of TNC images to replace VNC images, thereby reducing the radiation dose. Methods: A total of 69 patients with postoperative pathologically confirmed CRC at the West China Hospital of Sichuan University between May 2022 and April 2023 were enrolled in this cross-sectional study. The CT protocol included the acquisition of TNC images, arterial and portal venous phase images; the VNC images were reconstructed from the two postcontrast phase images. Several parameters, including the CT attenuation value, absolute attenuation error, imaging noise [standard deviation (SD)], signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR), were measured in multiple abdominal structures for both the TNC and VNC images. Two blinded readers assessed the subjective image quality using a five-point scale. Interobserver agreement was evaluated using interclass correlation coefficients (ICCs). The paired t-test and Wilcoxon signed-rank test were used to compare the objective and subjective results between the TNC and VNC images. Individual measurements of radiation doses for the TNC scan and contrast scan protocols were recorded. Results: A total of 2,070 regions of interest (ROIs) of the 69 patients were analyzed. Overall, the VNC images exhibited significantly lower attenuation values and SD values than the TNC images in all tissues, except for the abdominal aorta, portal vein, and spleen. The mean absolute attenuation errors between the VNC and TNC images were all less than 10 Hounsfield units (HU). The percentages of absolute attenuation errors less than 5 and 10 HU in the VNC images from the arterial phase (VNCa) were 78.99% and 97.97%, respectively, while those from the portal venous phase (VNCp) were 81.59% and 96.96%, respectively. The absolute attenuation errors between the TNC and VNCa images were smaller than those between the TNC and VNCp images for tumors [VNCaerror: 2.77, interquartile range (IQR) 1.77-4.22; VNCperror: 3.27, IQR 2.68-4.30; P=0.002]. The SNR values and CNR values in the VNC images were significantly higher than those in the TNC images for all tissues, except for the portal vein and spleen. The image quality was rated as excellent (represented by a score of 5) in the majority of the TNC and VNC images; however, the VNC images scored lower than the TNC images. Eliminating the TNC phase resulted in a reduction of approximately 37.99% in the effective dose (ED). Conclusions: The VNC images provided accurate CT attenuation, good image quality, and lower radiation doses than the TNC images in CRC, and the VNCa images showed minimal differences in the CT attenuation of the tumors.

The addition of nimotuzumab during concurrent chemoradiotherapy improved survival outcomes in locally advanced nasopharyngeal carcinoma patients with optimal response to induction chemotherapy.

OBJECTIVE: To investigate the impact of response to induction chemotherapy (IC) on survival outcomes in patients with locally advanced nasopharyngeal carcinoma (LANPC) and evaluate the efficacy of adding nimotuzumab to concurrent chemoradiotherapy (CCRT) based on different responses to IC. METHODS: We retrospectively included patients with stage III-IVA NPC who underwent IC with and without nimotuzumab during CCRT. Statistical analysis included the chi-square test, propensity score matching, Kaplan-Meier survival analysis, and Cox proportional hazards model. RESULTS: Among 383 identified patients, 216 (56.4%) received nimotuzumab during CCRT, while 167 (43.6%) did not. Following IC, 269 (70.2%) patients showed a complete response (CR) or partial response (PR), and 114 (29.8%) had stable disease (SD) or progressive disease (PD). The response to IC independently influenced disease-free survival (DFS) and overall survival (OS). Patients achieving CR/PR demonstrated significantly higher 3-year DFS (80.3% vs. 70.6%, P = 0.031) and OS (90.9% vs. 83.2%, P = 0.038) than those with SD/PD. The addition of nimotuzumab during CCRT significantly improved DFS (P = 0.006) and OS (P = 0.037) for CR/PR patients but not for those with SD/PD. CONCLUSIONS: This study emphasizes the importance of IC response in LANPC and highlights the potential benefits of nimotuzumab during CCRT for improving survival outcomes in CR/PR patients. Tailored treatment approaches for SD/PD patients warrant further investigation.

Small-molecule-based targeted therapy in liver cancer.

Liver cancer is one of the most prevalent malignant tumors worldwide. According to the Barcelona Clinic Liver Cancer staging criteria, clinical guidelines provide tutorials to clinical management of liver cancer at their individual stages. However, most patients diagnosed with liver cancer are at advanced stage; therefore, many researchers conduct investigations on targeted therapy, aiming to improve the overall survival of these patients. To date, small-molecule-based targeted therapies are highly recommended (first line: sorafenib and lenvatinib; second line: regorafenib and cabozantinib) by current the clinical guidelines of the American Society of Clinical Oncology, European Society for Medical Oncology, and National Comprehensive Cancer Network. Herein, we summarize the small-molecule-based targeted therapies in liver cancer, including the approved and preclinical therapies as well as the therapies under clinical trials, and introduce their history of discovery, clinical trials, indications, and molecular mechanisms. For drug resistance, the revealed mechanisms of action and the combination therapies are also discussed. In fact, the known small-molecule-based therapies still have limited clinical benefits to liver cancer patients. Therefore, we analyze the current status and give our ideas for the urgent issues and future directions in this field, suggesting clues for novel techniques in liver cancer treatment.

Design, synthesis, and hypoxia-inducible factor-1α inhibitory activity evaluation of panaxadiol derivatives containing a thiazole moiety.

The hypoxia-inducible factor-1α (HIF-1α) pathway has been implicated in tumor angiogenesis, growth, and metastasis. Therefore, the inhibition of this pathway is an important therapeutic target for cancer. Here, three series of panaxadiol derivatives containing a thiazole moiety (5a-l, 7a-i, and 9a-i) were synthesized and evaluated for HIF-1α inhibitory activity using a Hep3B cell-based luciferase reporter assay. Compounds 5d and 7b showed the strongest inhibitory activity with IC50 values of 17.37 and 6.42 µM, respectively, and did not show any significant cytotoxicity. Western blot assay results indicated that these two compounds exhibited more potent inhibition, compared with panaxadiol, of the expression of HIF-1α protein in Hep3B cells at a concentration of 50 µM. Molecular docking experiments were also performed to investigate the structure-activity relationship.

Novel humanized monoclonal antibodies against ROR1 for cancer therapy.

BACKGROUND: Overexpression of receptor tyrosine kinase-like orphan receptor 1 (ROR1) contributes to cancer cell proliferation, survival and migration, playing crucial roles in tumor development. ROR1 has been proposed as a potential therapeutic target for cancer treatment. This study aimed to develop novel humanized ROR1 monoclonal antibodies and investigate their anti-tumor effects. METHODS: ROR1 expression in tumor tissues and cell lines was analyzed by immunohistochemistry and flow cytometry. Antibodies from mouse hybridomas were humanized by the complementarity-determining region (CDR) grafting technique. Surface plasmon resonance spectroscopy, ELISA assay and flow cytometry were employed to characterize humanized antibodies. In vitro cellular assay and in vivo mouse experiment were conducted to comprehensively evaluate anti-tumor activity of these antibodies. RESULTS: ROR1 exhibited dramatically higher expression in lung adenocarcinoma, liver cancer and breast cancer, and targeting ROR1 by short-hairpin RNAs significantly inhibited proliferation and migration of cancer cells. Two humanized ROR1 monoclonal antibodies were successfully developed, named h1B8 and h6D4, with high specificity and affinity to ROR1 protein. Moreover, these two antibodies effectively suppressed tumor growth in the lung cancer xenograft mouse model, c-Myc/Alb-cre liver cancer transgenic mouse model and MMTV-PyMT breast cancer mouse model. CONCLUSIONS: Two humanized monoclonal antibodies targeting ROR1, h1B8 and h6D4, were successfully developed and exhibited remarkable anti-tumor activity in vivo.