Clinical immunotherapy in pancreatic cancer.

Pancreatic cancer remains a challenging disease with limited treatment options, resulting in high mortality rates. The predominant approach to managing pancreatic cancer patients continues to be systemic cytotoxic chemotherapy. Despite substantial advancements in immunotherapy strategies for various cancers, their clinical utility in pancreatic cancer has proven less effective and durable. Whether administered as monotherapy, employing immune checkpoint inhibitors, tumor vaccines, chimeric antigen receptors T cells, or in combination with conventional chemoradiotherapy, the clinical outcomes remain underwhelming. Extensive preclinical experiments and clinical trials in the realm of pancreatic cancer have provided valuable insights into the complexities of immunotherapy. Chief among the hurdles are the immunosuppressive tumor microenvironment, limited immunogenicity, and the inherent heterogeneity of pancreatic cancer. In this comprehensive review, we provide an overview and critical analysis of current clinical immunotherapy strategies for pancreatic cancer, emphasizing their endeavors to overcome immunotherapy resistance. Particular focus is placed on strategies aimed at reshaping the immunosuppressive microenvironment and enhancing T cell-mediated tumor cell killing. Ultimately, through deeper elucidation of the underlying pathogenic mechanisms of pancreatic cancer and the refinement of therapeutic approaches, we anticipate breakthroughs that will pave the way for more effective treatments in this challenging disease.

Peroxide-Simulating and GSH-Depleting Nanozyme for Enhanced Chemodynamic/Photodynamic Therapy via Induction of Multisource ROS.

Reactive oxygen species (ROS) generation, using photodynamic therapy (PDT) and chemodynamic therapy (CDT), is a promising strategy for cancer treatment. However, the production of ROS in tumor cells is often limited by hypoxia, insufficient substrates, and high level of ROS scavengers in a tumor microenvironment, which seriously affects the efficacy of ROS-related tumor therapies. Herein, we report a lipid-supported manganese oxide nanozyme, MLP@DHA&Ce6, by decorating a MnO2 nano-shell on the liposome loaded with dihydroartemisinin (DHA) and photosensitizer Ce6 for generating multisource ROS to enhance cancer therapy. MLP@DHA&Ce6 can be accumulated in tumors and can release active components, Mn2+ ions, and O2. The conjugate generates ROS via nanozyme-catalyzed CDT using DHA as a substrate, PDT through Ce6, and the Fenton reaction catalyzed by Mn2+ ions. The production of O2 from MnO2 enhanced Ce6-mediated PDT under near-infrared light irradiation. Meanwhile, MLP@DHA&Ce6 showed prominent glutathione depletion, which allowed ROS to retain high activity in tumor cells. In addition, the release of Mn2+ ions and DHA in tumor cells induced ferroptosis. This multisource ROS generation and ferroptosis effect of MLP@DHA&Ce6 led to enhanced therapeutic effects in vivo.

A Novel Closed-Loop Structure for Drag-Free Control Systems with ESKF and LQR.

Space-borne gravitational wave detection satellite confronts many uncertain perturbations, such as solar pressure, dilute atmospheric drag, etc. To realize an ultra-static and ultra-stable inertial benchmark achieved by a test-mass (TM) being free to move inside a spacecraft (S/C), the drag-free control system of S/C requires super high steady-state accuracies and dynamic performances. The Active Disturbance Rejection Control (ADRC) technique has a certain capability in solving problems with common perturbations, while there is still room for optimization in dealing with the complicated drag-free control problem. When faced with complex noises, the steady-state accuracy of the traditional control method is not good enough and the convergence speed of regulating process is not fast enough. In this paper, the optimized Active Disturbance Rejection Control technique is applied. With the extended state Kalman filter (ESKF) estimating the states and disturbances in real time, a novel closed-loop control structure is designed by combining the linear quadratic regulator (LQR) and ESKF, which can satisfy the design targets competently. The comparative analysis and simulation results show that the LQR controller designed in this paper has a faster response and a higher accuracy compared with the traditional nonlinear state error feedback (NSEF), which uses a deformation of weighting components of classical PID. The new drag-free control structure proposed in the paper can be used in future gravitational wave detection satellites.

Telomere in colorectal cancer associated with distant metastases and predicted a poor prognosis.

BACKGROUND: Telomere is essential for chromosomal stability and its length has been proven to be related to prognosis in many malignant tumors. This study aims to investigate the relevance of telomere length with clinical and pathologic features and its prognostic value in colorectal cancer (CRC). METHODS: Telomere status of CRC and adenoma cells were measured by telomere-specific quantitative fluorescent in situ hybridization (Q-FISH). The relative telomere length (RTL) was calculated as the mean telomere fluorescent intensity units (TFUs) in carcinoma cell divided by the TFU in cancer-associated fibroblast cell (CAF). RESULTS: One hundred CRC patients, who were received surgery treatment during 2013 to 2014 and fifty-seven patients who underwent the examination of colonoscope and were confirmed as adenoma were enrolled. TFUs of carcinoma cell and CAF were statistically significantly lower than in adjacent mucosa cell (P=0.0079). Although there was no difference between the three kinds of adenoma cells (P=0.5457), TFU in adenoma cells was significantly lower than in CAF (P<0.0001) and independent with age. TFU and the RTL were statistically significantly lower in adenoma cells than in carcinoma (all P<0.0001). TFU of carcinoma cell in distant metastases patients were significantly lower than that without distant metastases patients (P=0.002). When cut by the median value of TFU of carcinoma cell and RTL, patients with a lower TFU or RTL had statistically significantly poorer overall survival (OS) (P=0.0027, HR: 4.6, 95% CI: 1.9-11.0; P=0.0163, HR: 2.95, 95% CI: 1.22-7.12) and disease-free survival (DFS) (P=0.0057, HR: 3.14, 95% CI: 1.40-7.06; P=0.0271, HR: 2.49, 95% CI: 1.11-5.59, respectively) than those patients with higher TFU or RTL. On multivariate analysis, the TFU of carcinoma cell was proved to be an independent prognostic value both for OS and DFS (P=0.0005, HR: 4.975, 95% CI: 1.616-15.385; P=0.007, HR: 3.57, 95% CI: 1.410-9.010). CONCLUSIONS: The length of telomere in carcinoma and adenoma cells were consistently shorter and the telomere changes were early carcinogenesis event, even the epithelial cells were morphologically not malignant. The length of telomere was associated with tumor metastases and prognosis, suggesting telomere probably was an important cue of the biological behavior of CRC.

Frequency, prognosis and treatment modalities of newly diagnosed small bowel cancer with liver metastases.

BACKGROUND: Population-based analysis for the liver metastases of small bowel cancer is currently lacking. This study aimed to analyze the frequency, prognosis and treatment modalities for newly diagnosed small bowel cancer patients with liver metastases. METHODS: Patients with small bowel cancer diagnosed from 2010 to 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Binary logistic regression analysis was performed to determine predictors for the presence of liver metastases at diagnosis. Kaplan-Meier method and Cox regression analyses were performed for survival analyses. RESULTS: A total of 1461 small bowel cancer patients with liver metastases at initial diagnosis were identified, representing 16.5% of the entire set and 63.9% of the subset with metastatic disease to any distant site. Primary tumor with poorer histological type, larger tumor size, later N staging, more extrahepatic metastatic sites, and tumor on lower part of small intestine had increased propensity of developing liver metastases. The combined diagnostic model exhibited acceptable diagnostic efficiency with AUC value equal to 0.749. Patients with liver metastases had significant poorer survival (P < 0.001) than those without liver metastases. In addition, combination of surgery and chemotherapy (HR = 0.27, P < 0.001) conferred the optimal survival for patients with adenocarcinoma, while the optimal treatment options for NEC and GIST seemed to be surgery alone (HR = 0.24, P < 0.001) and chemotherapy alone (HR = 0.08, P = 0.022), respectively. CONCLUSIONS: The combined predictor had a good ability to predict the presence of liver metastases. In addition, those patients with different histologic types should be treated with distinct therapeutic strategy for obtaining optimal survival.