Clinical Efficacy of Taxol Plus Platinum (TP) Chemotherapy Combined with Delayed Administration of PD-1 Inhibitors in Patients with Locally Advanced, Recurrent or Metastatic Esophageal Squamous Cell Carcinoma: A Retrospective Study.

Purpose: Immune checkpoint inhibitors (ICIs) combined with chemotherapy have become the first-line standard treatment for locally advanced or metastatic esophageal squamous cell carcinoma (ESCC). The evidence also demonstrates improved synergistic effects of chemotherapy when combined with delayed administration of ICIs. In this study, we conducted a retrospective investigation into the treatment efficacy of taxol plus platinum (TP) chemotherapy combined with delayed administration of PD-1 inhibitors for ESCC patients. Patients and Methods: Clinical data of ESCC patients who received PD-1 inhibitors 3-5 days after TP chemotherapy as first-line treatment was retrospectively reviewed between January 2019 and April 2023. Clinical outcomes and treatment safety were analyzed. The potential roles of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), and pan-immune-inflammation value (PIV) were investigated. Results: A total of 34 locally advanced, recurrent or metastatic ESCC patients received PD-1 inhibitors 3-5 days following TP chemotherapy were included. The objective response rate (ORR) and disease control rate (DCR) were 85.3% and 97.1% respectively. The median progression-free survival (PFS) and overall survival (OS) were 13.2 and 19.1 month respectively. Seven patients received radical surgery, 1 patient achieved pathologic complete response (pCR) and 3 patients achieved major pathologic response (MPR). Among the 27 patients without surgery, the median PFS and OS were 9.7 and 19.1 month respectively. A more favorable prognosis was correlated with NLR less than 3 at the 3rd and 4th cycle of immunochemotherapy. No significant correlations between other parameters (PLR, MLR and PIV) and prognosis were observed. A total of 22 patients developed grade 3-4 toxicity events. Conclusion: The optimized sequence of PD-1 inhibitors administered 3-5 days after TP chemotherapy as the first-line treatment of ESCC demonstrated favorable treatment efficacy. Pretreatment NLR of less than 3 at the 3rd and 4th cycle of immunochemotherapy is associated with a better prognosis.

Impact and mechanisms of drag-reducing polymers on shear stress regulation in pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH) is a refractory disease characterized by elevated pulmonary artery pressure and resistance. Drag-reducing polymers (DRPs) are blood-soluble macromolecules that reduce vascular resistance by altering the blood dynamics and rheology. Our previous work indicated that polyethylene oxide (PEO) can significantly reduce the medial wall thickness and vascular resistance of the pulmonary arteries, but the specific mechanism is still unclear. METHODS: This study was designed to investigate the role and mechanism of PEO on intracellular calcium [Ca2 +] i and cytoskeletal proteins of endothelial cells (ECs) induced by low shear stress (LSS) in PH. Primary Pulmonary Artery Endothelial Cells (PAECs) were subjected to steady LSS (1 dyn/cm2) or physiological shear stress (SS) (10 dyn/cm2) for 20 h in a BioFlux 200 flow system. Calcium influx assays were conducted to evaluate the mechanisms of PEO on [Ca2 +] i. Subsequently, taking the key protein that induces cytoskeletal remodeling, the regulatory light chain (RLC) phosphorylation, as the breakthrough point, this study focused on the two key pathways of PEO that regulate phosphorylation of RLC: Myosin light chain kinase (MLCK) and Rho-associated kinase (ROCK) pathways. RESULTS: Our current research revealed that PEO at LSS (1 dyn/cm2) significantly suppressed LSS-induced [Ca2 +] i and the expression level of transient receptor potential channel 1(TRPC1). In addition, ECs convert LSS stimuli into the upregulation of cytoskeletal proteins, including filamentous actin (F-actin), MLCK, ROCK, p-RLC, and pp-RLC. Further experiments using pharmacological inhibitors demonstrated that PEO at the LSS downregulated cytoskeleton-related proteins mainly through the ROCK and MLCK pathways. CONCLUSIONS: This study considered intracellular calcium and cytoskeleton rearrangement as entry points to study the application of PEO in the biomedical field, which has important theoretical significance and practical application value for the treatment of PH.

High core 1ß1,3-galactosyltransferase 1 expression is associated with poor prognosis and promotes cellular radioresistance in lung adenocarcinoma.

PURPOSE: Core 1ß1,3-galactosyltransferase 1 (C1GALT1) exhibits elevated expression in multiple cancers. The present study aimed to elucidate the clinical significance of C1GALT1 aberrant expression and its impact on radiosensitivity in lung adenocarcinoma (LUAD). METHODS: The C1GALT1 expression and its clinical relevance were investigated through public databases and LUAD tissue microarray analyses. A549 and H1299 cells with either C1GALT1 knockdown or overexpression were further assessed through colony formation, gamma-H2A histone family member X immunofluorescence, 5-ethynyl-2'-deoxyuridine incorporation, and flow cytometry assays. Bioinformatics analysis was used to explore single cell sequencing data, revealing the influence of C1GALT1 on cancer-associated cellular states. Vimentin, N-cadherin, and E-cadherin protein levels were measured through western blotting. RESULTS: The expression of C1GALT1 was significantly higher in LUAD tissues than in adjacent non-tumor tissues both at mRNA and protein level. High expression of C1GALT1 was correlated with lymph node metastasis, advanced T stage, and poor survival, and was an independent risk factor for overall survival. Radiation notably upregulated C1GALT1 expression in A549 and H1299 cells, while radiosensitivity was increased following C1GALT1 knockdown and decreased following overexpression. Experiment results showed that overexpression of C1GALT1 conferred radioresistance, promoting DNA repair, cell proliferation, and G2/M phase arrest, while inhibiting apoptosis and decreasing E-cadherin expression, alongside upregulating vimentin and N-cadherin in A549 and H1299 cells. Conversely, C1GALT1 knockdown had opposing effects. CONCLUSION: Elevated C1GALT1 expression in LUAD is associated with an unfavorable prognosis and contributes to increased radioresistance potentially by affecting DNA repair, cell proliferation, cell cycle regulation, and epithelial-mesenchymal transition (EMT).