Monocarboxylate transporter upregulation in induced regulatory T cells promotes resistance to anti-PD-1 therapy in hepatocellular carcinoma patients

BackgroundProgrammed cell death-1 (PD-1) immune checkpoint inhibitors are not effective in treating all patients with hepatocellular carcinoma (HCC), and regulatory T cells (Tregs) may determine the resistance to anti-PD-1 therapy.MethodsPatients were divided into two groups based on the clinical efficacy of anti-PD-1 therapy. Flow cytometry was used to determine the phenotype of CD4+, CD8+, and Tregs in peripheral blood mononuclear cells (PBMCs). CD4+CD45RA+T cells were sorted to analyze Treg differentiation and function.ResultsNo significant differences were found between resistant and sensitive patients in the percentage of CD4+ T cells and Tregs in PBMCs or the differentiation and function of induced Tregs (iTregs). However, iTregs from resistant patients presented higher monocarboxylate transporter (MCT) expression. Lactate induced more iTregs and improved OXPHOS levels in the resistant group. MCT1 and MCT2 were highly expressed in tumor-infiltrating Tregs, and patients with higher MCT1 expression had worse clinical outcomes. Combinatorial therapy with MCT antibody and anti-PD-1 therapy effectively inhibited tumor growth.ConclusionMCT and its downstream lactate signal in Tregs can confer anti-PD-1 resistance and may be a marker of poor prognosis in HCC

Static and Dynamic Characteristics of a Long-Span Cable-Stayed Bridge with CFRP Cables

In this study, the scope of CFRP cables in cable-stayed bridges is studied by establishing a numerical model of a 1400-m span of the same. The mechanical properties and characteristics of CFRP stay cables and of a cable-stayed bridge with CFRP cables are here subjected to comprehensive analysis. The anomalies in the damping properties of free vibration, nonlinear parametric vibration and wind fluctuating vibration between steel cables and CFRP cables are determined. The structural stiffness, wind resistance and traffic vibration of the cable-stayed bridge with CFRP cables are also analyzed. It was found that the static performances of a cable-stayed bridge with CFRP cables and steel cables are basically the same. The natural frequencies of CFRP cables do not coincide with the major natural frequencies of the cable-stayed bridge, so the likelihood of CFRP cable-bridge coupling vibration is minuscule. For CFRP cables, the response amplitudes of both parametric vibration and wind fluctuating vibration are smaller than those of steel cables. It can be concluded from the research that the use of CFRP cables does not change the dynamic characteristics of the vehicle-bridge coupling vibration. Therefore, they can be used in long-span cable-stayed bridges with an excellent mechanical performance

Large-Scale Preparation of Low-Cost Nonfullerene Acceptors for Stable and Efficient Organic Solar Cells

Despite the development of nonfullerene acceptors (NFAs) that have made a breakthrough in the photovoltaic performance, large-scale preparation of NFAs that is prerequisite for commercial application has never been explored. Herein, we designed two dodecacyclic all-fused-ring electron acceptors, F11 and F13, and develop a whole set of synthetic procedures, achieving unprecedented scalable preparation of NFAs in the lab at a 10-g scale notably within one day. The single-crystal structures of F11 reveals the 3D network packing. F11 and F13 display the lowest costs among reported NFAs, even comparable with the classical donor material, P3HT. By matching a medium-bandgap polymer donor, F13 delivers power conversion efficiencies of over 13%, which is an efficiency record for non-INCN acceptors. Benefiting from the intrinsically high stability, OSCs based on F11 and F13 show device stability superior to the typical ITIC- and Y6-based OSCs as evidenced by the tiny burn-in losses. The current work presents a first example for large-scale preparation of low-cost NFAs with good efficiency and high device stability, which is significant for OSC commercialization in near future

Fatigue Performance Assessment of Composite Arch Bridge Suspenders Based on Actual Vehicle Loads

In the through arch bridges, the suspenders are the key components connecting the arch rib and the bridge deck in the middle, and their safety is an increasing focus in the field of bridge engineering. In this study, various vehicle traffic flow parameters are investigated based on the actual vehicle data acquired from the long-term structural health monitoring system of a composite arch bridge. The representative vehicle types and the probability density functions of several parameters are determined, including the gross vehicle weight, axle weight, time headway, and speed. A finite element model of the bridge structure is constructed to determine the influence line of the cable force for various suspenders. A simulated vehicle flow, generated using the Monte Carlo method, is applied on the influence lines of the target suspender to determine the stress process, and then the stress amplitude spectrum is obtained based on the statistical analysis of the stress process using the rainflow counting method. The fatigue performance levels of various suspenders are analyzed according to the Palmgren-Miner linear cumulative damage theory, which helps to manage the safety of the suspenders

Orosomucoid 1 promotes colorectal cancer progression and liver metastasis by affecting PI3K/AKT pathway and inducing macrophage M2 polarization

Abstract Approximately 25–30% of those affected by colorectal cancer (CRC), the most prevalent gastrointestinal malignancy, develop metastases. The survival rate of patients with liver metastasis of CRC (CRLM) remains low owing to its unpredictability and a lack of biomarkers that can be applied to distinguish groups at higher risk for CRLM among patients with CRC. Therefore, our study aimed to find biomarkers that can predict the risk of CRLM. Screening of the Gene Expression Omnibus database, supported by an analysis of clinically obtained tissue and serum data using qPCR and ELISA, in an attempt to identify relevant biomarkers, enabled us to determine that orosomucoid 1 (ORM1) was differentially expressed in liver metastases and primary tumors of patients with CRC. Functionally, overexpression of ORM1 promoted the epithelial-mesenchymal transition and the proliferative, migratory, and invasive activities of MC38 cells and activated the PI3K/AKT signaling pathway. Moreover, MC38 cells overexpressing ORM1 enhanced the tumor immune microenvironment by promoting macrophage M2 polarization and elevating interleukin-10 (IL-10) expression. In vivo experiments further confirmed in vitro results, indicating that liver metastases elevated by ORM1 were partially attenuated by the depletion of macrophages or IL-10. Considered together, ORM1 promotes CRC progression and liver metastasis by regulating tumor cell growth and inducing macrophage M2 polarization, which mediates tumor immune tolerance, and thus acts as a potential predictive marker and therapeutic target in CRLM

miR-455/GREM1 axis promotes colorectal cancer progression and liver metastasis by affecting PI3K/AKT pathway and inducing M2 macrophage polarization

Abstract Background Colorectal cancer is among the most common malignant tumors affecting the gastrointestinal tract. Liver metastases, a complication present in approximately 50% of colorectal cancer patients, are a considerable concern. Recently, studies have revealed the crucial role of miR-455 in tumor pathogenesis. However, the effect of miR-455 on the progression of liver metastases in colorectal cancer remains controversial. As an antagonist of bone morphogenetic protein(BMP), Gremlin 1 (GREM1) may impact organogenesis, body patterning, and tissue differentiation. Nevertheless, the role of miR-455 in regulating GREM1 in colorectal cancer liver metastases and how miR-455/GREM1 axis influences tumour immune microenvironment is unclear. Methods Bioinformatics analysis shows that miR-455/GREM1 axis plays crucial role in liver metastasis of intestinal cancer and predicts its possible mechanism. To investigate the impact of miR-455/GREM1 axis on the proliferation, invasion, and migration of colorectal cancer cells, colony formation assay, wound healing and transwell assay were examined in vitro. The Dual-Luciferase reporter gene assay and RNA pull-down assay confirmed a possible regulatory effect between miR-455 and GREM1. In vivo, colorectal cancer liver metastasis(CRLM) model mice was established to inquiry the effect of miR-455/GREM1 axis on tumor growth and macrophage polarization. The marker of macrophage polarization was tested using immunofluorescence(IF) and quantitative real-time polymerase chain reaction(qRT-PCR). By enzyme-linked immunosorbent assay (ELISA), cytokines were detected in culture medium supernatants. Results We found that miR-455 and BMP6 expression was increased and GREM1 expression was decreased in liver metastase compared with primary tumor. miR-455/GREM1 axis promotes colorectal cancer cells proliferation, migration, invasion via affected PI3K/AKT pathway. Moreover, downregulating GREM1 augmented BMP6 expression in MC38 cell lines, inducing M2 polarization of macrophages, and promoting liver metastasis growth in CRLM model mice. Conclusion These data suggest that miR-455/GREM1 axis promotes colorectal cancer progression and liver metastasis by affecting PI3K/AKT pathway and inducing M2 macrophage polarization. These results offer valuable insights and direction for future research and treatment of CRLM

Cathode interfacial layer-free all small-molecule solar cells with efficiency over 12%

While nonfullerene small-molecule solar cells (NF-SMSCs) have relatively inferior performance compared with nonfullerene polymer solar cells, their performance is improving. In this work, a weak crystalline molecular donor BSFTR, was designed and synthesized to achieve efficient NF-SMSCs. By blending with a strong crystalline acceptor NBDTP-F-out, BSFTR achieves a well-intermixed blending morphology, which favors the formation of efficient charge percolation pathways with suppressed recombination. The BSFTR:NBDTP-F-out device obtains a power-conversion efficiency (PCE) of approximately 11.97% by achieving an efficient cathode interfacial layer (CIL)-free device that delivers an even higher PCE of 12.3%, which ranks among the top values for the reported NF-SMSCs. This work provides a simple solution for achieving high-performance NF-SMSCs by identifying the key factors for designing efficient, cost-saving, mass production-favorable CIL-free organic photovoltaic devices

Revealing the Critical Role of the HOMO Alignment on Maximizing Current Extraction and Suppressing Energy Loss in Organic Solar Cells

For state-of-the-art organic solar cells (OSCs) consisting of a large-bandgap polymer donor and a near-infrared (NIR) molecular acceptor, the control of the HOMO offset is the key to simultaneously achieve small energy loss (Eloss) and high photocurrent. However, the relationship between HOMO offsets and the efficiency for hole separation is quite elusive so far, which requires a comprehensive understanding on how small the driving force can effectively perform the charge separation while obtaining a high photovoltage to ensure high OSC performance. By designing a new family of ZITI-X NIR acceptors (X = S, C, N) with a high structural similarity and matching them with polymer donor J71 forming reduced HOMO offsets, we systematically investigated and established the relationship among the photovoltaic performance, energy loss, and hole-transfer kinetics. We achieved the highest PCEavgs of 14.05 ± 0.21% in a ternary system (J71:ZITI-C:ZITI-N) that best optimize the balance between driving force and energy loss

Suppressing electron-phonon coupling in organic photovoltaics for high-efficiency power conversion

Abstract The nonradiative energy loss (∆E nr) is a critical factor to limit the efficiency of organic solar cells. Generally, strong electron-phonon coupling induced by molecular motion generates fast nonradiative decay and causes high ∆E nr. How to restrict molecular motion and achieve a low ∆E nr is a sticking point. Herein, the free volume ratio (FVR) is proposed as an indicator to evaluate molecular motion, providing new molecular design rationale to suppress nonradiative decay. Theoretical and experimental results indicate proper proliferation of alkyl side-chain can decrease FVR and restrict molecular motion, leading to reduced electron-phonon coupling while maintaining ideal nanomorphology. The reduced FVR and favorable morphology are simultaneously obtained in AQx-6 with pinpoint alkyl chain proliferation, achieving a high PCE of 18.6% with optimized V OC, J SC and FF. Our study discovered aggregation-state regulation is of great importance to the reduction of electron-phonon coupling, which paves the way to high-efficiency OSCs

Subtle Molecular Tailoring Induces Significant Morphology Optimization Enabling over 16% Efficiency Organic Solar Cells with Efficient Charge Generation

Manipulating charge generation in a broad spectral region has proved to be crucial for nonfullerene-electron-acceptor-based organic solar cells (OSCs). 16.64% high efficiency binary OSCs are achieved through the use of a novel electron acceptor AQx-2 with quinoxaline-containing fused core and PBDB-TF as donor. The significant increase in photovoltaic performance of AQx-2 based devices is obtained merely by a subtle tailoring in molecular structure of its analogue AQx-1. Combining the detailed morphology and transient absorption spectroscopy analyses, a good structure-morphology-property relationship is established. The stronger pi-pi interaction results in efficient electron hopping and balanced electron and hole mobilities attributed to good charge transport. Moreover, the reduced phase separation morphology of AQx-2-based bulk heterojunction blend boosts hole transfer and suppresses geminate recombination. Such success in molecule design and precise morphology optimization may lead to next-generation high-performance OSCs