ABSTRACT
The aim of this paper is to investigate the aging mechanism of asphalt in the sea salt erosion environment from a rheological point of view. In order to simulate the real pavement aging process in the sea salt erosion environment, base asphalt and Styrene-Butadiene-Styrene (SBS)-modified asphalt were selected for salt environment aging tests. The asphalt samples were aged via a thin film oven test (TFOT) and a pressure aging vessel (PAV) test. Then, thermo-oxidizing conditions were created after the samples were immersed in salt solution, mixed with four different concentrations of sodium chloride (NaCl) and sodium sulphate (Na2SO4), to investigate the aging state of asphalt. Temperature scan (TS), frequency scan (FS), and multiple stress creep and recovery (MSCR) tests performed using a Dynamic Shear Rheometer (DSR) were used to investigate the effects on the rheological properties of aged asphalt in a salt environment. The results showed that both base asphalt and SBS-modified asphalt were aged to different degrees under mixed salt solutions. The two asphalt samples aged in a salt environment showed increased hardness. SBS-modified asphalt exhibited higher aging resistance compared with base asphalt in the sea salt environment. However, due to the degradation of the SBS modifier and the aging of base asphalt, the properties of the SBS-modified asphalt showed more obvious complexity with changes in salt solution concentrations.
ABSTRACT
BACKGROUND & AIMS: Both nonalcoholic fatty liver disease (NAFLD) and colorectal cancer (CRC) are prevalent worldwide. The effects of concomitant NAFLD on the risk of colorectal liver metastasis (CRLM) and its mechanisms have not been definitively elucidated. METHODS: We observed the effect of concomitant NAFLD on CRLM in the mouse model and explored the underlying mechanisms of specific myeloid-derived suppressor cells (MDSCs) recruitment and then tested the therapeutic application based on the mechanisms. Finally we validated our findings in the clinical samples. RESULTS: Here we prove that in different mouse models, NAFLD induces F4/80+ Kupffer cells to secret chemokine CXCL5 and then recruits CXCR2+ MDSCs to promote the growth of CRLM. CRLM with NAFLD background is refractory to the anti-PD-1 monoclonal antibody treatment, but when combined with Reparixin, an inhibitor of CXCR1/2, dual therapy cures the established CRLM in mice with NAFLD. Our clinical studies also indicate that fatty liver diseases increase the infiltration of CXCR2+ MDSCs, as well as the hazard of liver metastases in CRC patients. CONCLUSIONS: Collectively, our findings highlight the significance of selective CXCR2+/CD11b+/Gr-1+ subset myeloid cells in favoring the development of CRLM with NAFLD background and identify a pharmaceutical medicine that is already available for the clinical trials and potential treatment.
Subject(s)
Chemokine CXCL5 , Colorectal Neoplasms , Disease Models, Animal , Liver Neoplasms , Myeloid-Derived Suppressor Cells , Non-alcoholic Fatty Liver Disease , Programmed Cell Death 1 Receptor , Receptors, Interleukin-8B , Animals , Colorectal Neoplasms/pathology , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/drug therapy , Liver Neoplasms/secondary , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Liver Neoplasms/drug therapy , Non-alcoholic Fatty Liver Disease/pathology , Non-alcoholic Fatty Liver Disease/metabolism , Non-alcoholic Fatty Liver Disease/drug therapy , Mice , Receptors, Interleukin-8B/metabolism , Receptors, Interleukin-8B/antagonists & inhibitors , Humans , Myeloid-Derived Suppressor Cells/metabolism , Myeloid-Derived Suppressor Cells/pathology , Myeloid-Derived Suppressor Cells/immunology , Chemokine CXCL5/metabolism , Programmed Cell Death 1 Receptor/metabolism , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Male , Cell Line, Tumor , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , Female , Kupffer Cells/metabolism , Kupffer Cells/pathology , Mice, Inbred C57BL , SulfonamidesABSTRACT
Notable-HCC (NCT05185531) is a phase 1b trial, aiming to evaluate the safety and preliminary effectiveness of neoadjuvant PD-1 blockade plus stereotactic body radiotherapy (SBRT) in early-stage resectable hepatocellular carcinoma (HCC). Twenty patients with HCC of BCLC stage 0-A received 3 × Gy SBRT and two cycles of tislelizumab, an anti-PD-1 monoclonal antibody before the curative HCC resection. Primary endpoints were the surgery delay, radiographic and pathological tumor response after the neoadjuvant therapy, safety and tolerability. During the neoadjuvant therapy, treatment-related adverse events (TRAEs) of grade 1-2 occurred in all 20 patients (100%), eight patients (40%) had grade 3 TRAEs, no grade 4 to 5 TRAE occurred, and all resolved without corticosteroids treatment. Per mRECIST, the objective response rate was 63.2% (12/19), with 3 complete response; the disease control rate was 100%. Two (10.5%) patients achieved complete pathological response. No surgery delay occurred. The neoadjuvant therapy did not increase the surgical difficulty or the incidence of complications. Secondary endpoints of disease-free survival and overall survival were not mature at the time of the analysis. Our pilot trial shows that neoadjuvant therapy with anti-PD-1 + SBRT is safe and promotes tumor responses in early-stage resectable HCC.
Subject(s)
Antibodies, Monoclonal, Humanized , Carcinoma, Hepatocellular , Liver Neoplasms , Radiosurgery , Humans , Neoadjuvant Therapy , Carcinoma, Hepatocellular/therapy , Carcinoma, Hepatocellular/pathology , Radiosurgery/adverse effects , Antineoplastic Combined Chemotherapy Protocols , Liver Neoplasms/therapy , Liver Neoplasms/pathology , Neoplasm Staging , Adjuvants, ImmunologicABSTRACT
AIM: To understand the proportion of uHCC (unresectable hepatocellular carcinoma) patients who achieve successful conversion resection in a high-volume setting with state of the art treatment options. METHODS: We retrospectively reviewed all HCC patients hospitalized to our center from June 1st, 2019 to June 1st, 2022. Conversion rate, clinicopathological features, response to systemic and/or loco-regional therapy and surgical outcomes were analyzed. RESULTS: A total of 1,904 HCC patients were identified, with 1672 patients receiving anti-HCC treatment. 328 patients were considered up-front resectable. Of the remaining 1344 uHCC patients, 311 received loco-regional treatment, 224 received systemic treatment, and the remainder (809) received combination systemic plus loco-regional treatment. Following treatment, one patient from the systemic group and 25 patients from the combination group were considered to have resectable disease. A high objective response rate (ORR) was observed in these converted patients (42.3% under RECIST v1.1 and 76.9% under mRECIST criteria). The disease control rate (DCR) reached 100%. 23 patients underwent curative hepatectomy. Major post-operative morbidity was equivalent in the both groups (P=0.76). Pathologic complete response (pCR) was 39.1%. During conversion treatment, grade 3 or higher treatment-related adverse events (TRAEs) were observed in 50% of patients. The median follow-up time was 12.9 months (range, 3.9~40.6) from index diagnosis and 11.4 months (range, 0.9~26.9) from resection. Three patients experienced disease recurrence following conversion surgery. CONCLUSIONS: By intensive treatment, a small sub-group of uHCC patients (2%) may potentially be converted to curative resection. Loco-regional combined with systemic modality was relative safe and effective in the conversion therapy. Short-term outcomes are encouraging, but long-term follow-up in a larger patient population are required to fully understand the utility of this approach.
