Arsenic trioxide augments immunogenic cell death and induces cGAS-STING-IFN pathway activation in hepatocellular carcinoma.

The treatment of hepatocellular carcinoma (HCC) is particularly challenging due to the inherent tumoral heterogeneity and easy resistance towards chemotherapy and immunotherapy. Arsenic trioxide (ATO) has emerged as a cytotoxic agent effective for treating solid tumors, including advanced HCC. However, its effectiveness in HCC treatment remains limited, and the underlying mechanisms are still uncertain. Therefore, this study aimed to characterize the effects and mechanisms of ATO in HCC. By evaluating the susceptibilities of human and murine HCC cell lines to ATO treatment, we discovered that HCC cells exhibited a range of sensitivity to ATO treatment, highlighting their inherent heterogeneity. A gene signature comprising 265 genes was identified to distinguish ATO-sensitive from ATO-insensitive cells. According to this signature, HCC patients have also been classified and exhibited differential features of ATO response. Our results showed that ATO treatment induced reactive oxygen species (ROS) accumulation and the activation of multiple cell death modalities, including necroptosis and ferroptosis, in ATO-sensitive HCC cells. Meanwhile, elevated tumoral immunogenicity was also observed in ATO-sensitive HCC cells. Similar effects were not observed in ATO-insensitive cells. We reported that ATO treatment induced mitochondrial injury and mtDNA release into the cytoplasm in ATO-sensitive HCC tumors. This subsequently activated the cGAS-STING-IFN axis, facilitating CD8+ T cell infiltration and activation. However, we found that the IFN pathway also induced tumoral PD-L1 expression, potentially antagonizing ATO-mediated immune attack. Additional anti-PD1 therapy promoted the anti-tumor response of ATO in ATO-sensitive HCC tumors. In summary, our data indicate that heterogeneous ATO responses exist in HCC tumors, and ATO treatment significantly induces immunogenic cell death (ICD) and activates the tumor-derived mtDNA-STING-IFN axis. These findings may offer a new perspective on the clinical treatment of HCC and warrant further study.

URI alleviates tyrosine kinase inhibitors-induced ferroptosis by reprogramming lipid metabolism in p53 wild-type liver cancers.

The clinical benefit of tyrosine kinase inhibitors (TKIs)-based systemic therapy for advanced hepatocellular carcinoma (HCC) is limited due to drug resistance. Here, we uncover that lipid metabolism reprogramming mediated by unconventional prefoldin RPB5 interactor (URI) endows HCC with resistance to TKIs-induced ferroptosis. Mechanistically, URI directly interacts with TRIM28 and promotes p53 ubiquitination and degradation in a TRIM28-MDM2 dependent manner. Importantly, p53 binds to the promoter of stearoyl-CoA desaturase 1 (SCD1) and represses its transcription. High expression of URI is correlated with high level of SCD1 and their synergetic expression predicts poor prognosis and TKIs resistance in HCC. The combination of SCD1 inhibitor aramchol and deuterated sorafenib derivative donafenib displays promising anti-tumor effects in p53-wild type HCC patient-derived organoids and xenografted tumors. This combination therapy has potential clinical benefits for the patients with advanced HCC who have wild-type p53 and high levels of URI/SCD1.

Tertiary lymphoid structures predict the prognosis and immunotherapy response of cholangiocarcinoma.

Introduction: Cholangiocarcinoma (CCA) is a malignant tumor of the biliary epithelium with a poor prognosis. The lack of biomarkers to predict therapeutic response and prognosis is one of the major challenges for CCA treatment. Tertiary lymphoid structures (TLS) provide a local and pivotal microenvironment for tumor immune responses. The prognostic value and clinical relevance of TLS in CCA remain unclear. We aimed to explore the characteristics and clinical significance of TLS in CCA. Methods: We investigated the prognostic value and clinical relevance of TLS in CCA using a surgery cohort containing 471 CCA patients (cohort 1) and an immunotherapy cohort containing 100 CCA patients (cohort 2). Hematoxylin and eosin (H&E) and immunohistochemical (IHC) staining were used to evaluate the maturity of TLS. Multiplex IHC (mIHC) was employed to characterize the composition of TLS. Results: Different maturity of TLS were observed in CCA tissue sections. Strong staining of the four-gene signature including PAX5, TCL1A, TNFRSF13C, and CD79A were found in TLS regions. A high density of intra-tumoral TLS (T-score high) were significantly correlated with longer overall survival (OS) both in CCA cohort 1 (p = 0.002) and cohort 2 (p = 0.01), whereas a high density of peri-tumoral TLS (P-score high) were associated with shorter OS in these two cohorts (p = 0.003 and p = 0.03, respectively). Conclusion: The established four-gene signature efficiently identified the TLS in CCA tissues. The abundance and spatial distribution of TLS were significantly correlated with the prognosis and immune checkpoint inhibitors (ICIs) immunotherapy response of CCA patients. The presence of intra-tumoral TLS are positive prognostic factors for CCA, which provide a theoretical basis for the future diagnosis and treatment of CCA.

Protective Role of Shenmai Injection on Radiation-Induced Heart Injury.

Radiation-induced heart injury (RIHI) limits the dose delivery of radiotherapy for thoracic cancer. Shenmai injection (SMI) is reported to have potential cytoprotective properties and is commonly used in cardiovascular diseases. So, we aimed to investigate the potential protective effects of SMI treatment on RIHI. In this study, we established the RIHI model using Sprague-Dawley rats and H9c2 cell line. In vivo, the biochemical assay was used to measure serum cardiac injury-related biomarkers and echocardiography to evaluate heart function. The pathological analysis was also applied to observe the myocardial structural changes. In vitro, we further measured the cell viability and reactive oxygen species (ROS) levels after irradiation with or without SMI treatment. Our data showed the administration of SMI reduced the level of serum cardiac injury biomarkers and ameliorated cardiac dysfunction after irradiation in rats. Pathological analysis revealed that SMI mitigated cardiac structural damage, fibrosis, and macrophage infiltration. Besides, treatment with SMI increased cell viability and decreased excess ROS production after irradiation in vitro. Taken together, our study demonstrated the protective role of SMI treatment on RIHI by inhibiting oxidative stress and decreasing structural remodeling.

STC2 activates PRMT5 to induce radioresistance through DNA damage repair and ferroptosis pathways in esophageal squamous cell carcinoma.

Radioresistance is the major reason for the failure of radiotherapy in esophageal squamous cell carcinoma (ESCC). Previous evidence indicated that stanniocalcin 2 (STC2) participates in various biological processes of malignant tumors. However, researches on its effect on radioresistance in cancers are limited. In this study, STC2 was screened out by RNA-sequencing and bioinformatics analyses as a potential prognosis predictor of ESCC radiosensitivity and then was determined to facilitate radioresistance. We found that STC2 expression is increased in ESCC tissues compared to adjacent normal tissues, and a higher level of STC2 is associated with poor prognosis. Also, STC2 mRNA and protein expression levels were higher in radioresistant cells than in their parental cells. Further investigation revealed that STC2 could interact with protein methyltransferase 5 (PRMT5) and activate PRMT5, thus leading to the increased expression of symmetric dimethylation of histone H4 on Arg 3 (H4R3me2s). Mechanistically, STC2 can promote DDR through the homologous recombination and non-homologous end joining pathways by activating PRMT5. Meanwhile, STC2 can participate in SLC7A11-mediated ferroptosis in a PRMT5-dependent manner. Finally, these results were validated through in vivo experiments. These findings uncovered that STC2 might be an attractive therapeutic target to overcome ESCC radioresistance.

The Natural History of Parapharyngeal Solitary Fibrous Tumor/Hemangiopericytoma: A Case Report.

Solitary fibrous tumor/hemangiopericytoma (SFT/HPC) is extremely rare, and most of them are immediately treated for radical resection. However, the information concerning its natural history remains unclear. In this report, we presented a patient with parapharyngeal SFT/HPC, who was not immediately treated with surgical resection at first diagnosis. After approximately 3 years, the tumor volume doubling time (TVDT) and specific growth rate (SGR) could be measured through 3 serial magnetic resonance imagings. The TVDTs in the early and late pretreatment stages were 350 and 180 days, respectively, while the SGRs were 0.002 and 0.003, respectively. The growth rate of this disease entity is generally slow and may accelerate in the disease process.

Ciclopirox Olamine Exerts Tumor-Suppressor Effects via Topoisomerase II Alpha in Lung Adenocarcinoma.

BACKGROUND: Globally, lung cancer is one of the most malignant tumors, of which lung adenocarcinoma (LUAD) is the most common subtype, with a particularly poor prognosis. Ciclopirox olamine (CPX) is an antifungal drug and was recently identified as a potential antitumor agent. However, how CPX and its mechanism of action function during LUAD remain unclear. METHODS: The effects of CPX on cell proliferation, cell cycle, reactive oxygen species (ROS) levels, and apoptosis were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, colony formation, western blotting, flow cytometry assays, and immunohistochemistry. Global gene expression levels were compared between control and CPX-treated LUAD cells. A LUAD xenograft mouse model was used to evaluate the potential in vivo effects of CPX. RESULTS: We observed that CPX displayed strong antitumorigenic properties in LUAD cells, inhibited LUAD proliferation, induced ROS production, caused DNA damage, and activated the ATR-CHK1-P53 pathway. Topoisomerase II alpha (TOP2A) is overexpressed in LUAD and associated with a poor prognosis. By analyzing differentially expressed genes (DEGs), TOP2A was significantly down-regulated in CPX-treated LUAD cells. Furthermore, CPX treatment substantially inhibited in vivo LUAD xenograft growth without toxicity or side effects to the hematological system and internal organs. CONCLUSIONS: Collectively, for the first time, we showed that CPX exerted tumor-suppressor effects in LUAD via TOP2A, suggesting CPX could potentially function as a promising chemotherapeutic for LUAD treatment.

Immobilization-assisted abdominal deep inspiration breath-hold in post-mastectomy radiotherapy of left-sided breast cancer with internal mammary chain coverage.

BACKGROUND: Whether to prophylactically irradiate the ipsilateral internal mammary chain (IMC) in post-mastectomy radiotherapy (PMRT) remains controversial because of equivocal clinical benefits against the added toxicities. Our previous study revealed that the cardiac dose was decreased during left-sided breast radiotherapy with abdominal deep inspiration breath-hold (aDIBH) as compared with free-breathing (FB) and thoracic deep inspiration breath-hold (tDIBH). Here we present the dosimetric advantage of aDIBH for patients undergoing PMRT with IMC coverage. METHODS: We prospectively analyzed 19 patients with left-sided breast cancer who underwent PMRT. Patients underwent computed tomography (CT) simulation under both free-breathing (FB) and aDIBH. The heart, left anterior descending coronary artery (LAD), lungs, and the contralateral breast was defined as organs at risk (OARs). Three-dimensional conformal radiation therapy (3D-CRT), inverse planning intensity-modulated radiation therapy (IMRT), and volumetric modulated arc therapy (VMAT) were used to calculate the doses received by both the planning target volume (PTV) and OARs, which were compared using the Wilcoxon signed-rank test. RESULTS: Compared with FB, the Dmean of the heart and LAD were respectively reduced by 3.5 Gy (P<0.003) and 8.9 Gy (P<0.001) in 3D-CRT, 2.6 Gy (P<0.001), and 7.8 Gy (P=0.001) in IMRT, 1.5 Gy (P<0.001) and 4.5 Gy (P=0.001) in VMAT plans under aDIBH. Among all these plans, the Dmean of the heart was lowest in aDIBH IMRT and 1.3 Gy lower than in aDIBH VMAT (P=0.002). aDIBH IMRT also resulted in a significantly reduced dose to the ipsilateral lung than plans under FB (P<0.05). Dmean and V5 to the contralateral lung and breast were higher in VMAT plans (P<0.05). CONCLUSIONS: Using an immobilization-assisted aDIBH technique, radiation doses to the heart can be kept at reasonably low levels even if IMC is included in the clinical target volume (CTV). Among 3D-CRT, IMRT, and VMAT plans, IMRT plus aDIBH results in the best heart-sparing effect. We recommend that the aDIBH technique be routinely applied in suitable patients if the IMC is irradiated.

Osalmid, a Novel Identified RRM2 Inhibitor, Enhances Radiosensitivity of Esophageal Cancer.

PURPOSE: Esophageal cancer (EC) is an aggressive malignancy and is often resistant to currently available therapies. Inhibition of ribonucleotide reductase small subunit M2 (RRM2) in tumors is speculated to mediate chemosensitization. Previous studies have reported that Osalmid could act as an RRM2 inhibitor. We explored whether RRM2 was involved in radioresistance and the antitumor effects of Osalmid in EC. METHODS AND MATERIALS: RRM2 expression was detected by immunohistochemistry in EC tissues. The effects of Osalmid on cell proliferation, apoptosis, and cell cycle were assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphhenyl tetrazolium, colony formation, and flow cytometry assays. DNA damage, cell apoptosis, and senescence induced by Osalmid or ionizing radiation (IR) alone, or both, were detected with immunofluorescence, flow cytometry, Western blot, and ß-galactosidase staining. A xenograft mouse model of EC was used to investigate the potential synergistic effects of Osalmid and IR in vivo. RESULTS: The expression of RRM2 in treatment-resistant EC tissues is much higher than in treatment-sensitive EC, and strong staining of RRM2 was correlated with shorter overall survival. We observed direct cytotoxicity of Osalmid in EC cells. Osalmid also produced inhibition of the ERK1/2 signal transduction pathway and substantially enhanced IR-induced DNA damage, apoptosis, and senescence. Furthermore, treatment with Osalmid and IR significantly suppressed tumor growth in xenograft EC models without additional toxicity to the hematologic system and internal organs. CONCLUSIONS: Our study revealed that RRM2 played a vital role in radioresistance in EC, and Osalmid synergized with IR to exert its antitumor effects both in vitro and in vivo.

Mucinous Prostate Cancer Shows Similar Prognosis to Typical Prostate Acinar Carcinoma: A Large Population-Based and Propensity Score-Matched Study.

Background: Mucinous prostate cancer (PCa) is an extremely rare form of prostate malignancy. To date, the limited knowledge of its biology and outcomes stems from mostly small, single institution experiences. We analyzed the Surveillance, Epidemiology, and End Results (SEER) database to explore the incidence and treatment of mucinous PCa together with its prognostic factors to gain relatively large and consolidated insights. Methods: Age-adjusted incidence (AAI) rates were evaluated over time. Propensity score matching (PSM) and Kaplan-Meier analyses were used to compare the prognosis between mucinous PCa and typical prostate acinar adenocarcinoma. We assessed cancer-specific survival (CSS) and overall survival (OS) after patient stratification according to summary stage and treatment choice. Cox hazards regression analysis was performed to determine independent predictors of CSS and OS. Results: The AAI in 2016 was 0.24 per million. Patients with mucinous PCa had similar CSS and OS to matched individuals with typical prostate acinar adenocarcinoma. In terms of treatment, 65.3% of mucinous PCa patients underwent surgery, and 23.9% received radiation therapy. Patients who underwent surgery had longer survival (CSS, p = 0.012; OS, p < 0.001), and patients who received radiation therapy had similar survival to those who did not receive radiation therapy (CSS, p = 0.794; OS, p = 0.097). A multivariate Cox analysis for CSS and OS showed that older age (CSS: HR: 4.982, p = 0.001; OS: HR: 4.258, p < 0.001) and distant stage (CSS: HR: 40.224, p < 0.001; OS: HR: 9.866, p < 0.001) were independent prognostic factors for mucinous PCa patients. Conclusions: Mucinous PCa has an extremely low AAI. Analysis of its outcomes indicates that it is not a more malignant tumor as previously suspected. Mucinous PCa shows a similar prognosis to typical prostate acinar carcinoma. Surgery was associated with prolonged survival. An older age at diagnosis and distant stage was associated with poor survival.