GDF15 as a Potential Target for Overcoming Cancer-Associated Fibroblast Mediated Treatment Resistance in Esophageal Adenocarcinoma

Background: Esophageal cancer (EC) ranks as the 7th most common cancer and 6th leading cause of cancer-related deaths worldwide. The standard treatment for locally advanced EC involves neoadjuvant chemoradiotherapy (NCRT)/neoadjuvant chemotherapy (NT) followed by surgery. Cancer-associated fibroblasts (CAFs) play a pivotal role and contribute to various aspects of tumor initiation and progression within the tumor microenvironment (TME). We aim to compare the effectiveness of NCRT and NCT in treating EC patients and to explore the molecular mechanisms underlying treatment resistance in esophageal adenocarcinoma (EAC), with a specific focus on the involvement of CAFs. Methods: A network meta-analysis was performed to compare the effectiveness of NCRT, NCT, and surgery alone in randomized control trials (RCTs) published up to September 2021. EAC CAFs and EAC patient-derived organoids (PDOs) were established from primary patient tissues. Transcriptomic analysis was used to identify potential factors that were involved in CAF-tumor interaction. Lentiviral transduction was conducted to establish stable GDF15 knockdown EAC cells and CAFs. In vitro cell viability assays and apoptosis analysis were performed to assess the sensitivity of EAC cells to chemotherapy and radiotherapy. GDF15 concentration was determined using ELISA. To validate CAF-mediated EAC tumor progression, we utilized EAC PDOs and paired CAFs as an ex vivo preclinical model. The prognostic value of GDF15 was assessed using our in-house data and externally validated through public databases. Results: 25 RCTs with 4563 EC patients were included in the network meta-analysis. NCRT improved overall survival (OS) compared to NCT (HR: 0.83, 95%CrI: 0.69-0.99) and surgery alone (HR: 0.72, 95%CrI: 0.63-0.82). In vitro studies demonstrated that CAFs promoted EAC chemotherapy resistance and radiotherapy resistance. Transcriptomic analysis revealed the enrichment of GDF15 in the EAC tumor-CAF transwell co-culture system, showing opposite expression patterns between tumor and CAF cells. GDF15 concentration was significantly elevated in the co-culture medium. Knockdown of GDF15 in OE33 and OE19 cells restored treatment sensitivity against chemotherapy and radiotherapy. Similar results were obtained when OE33 and OE19 cells were co-cultured with GDF15-depleted CAFs. In the 3D EAC PDO model, enhanced chemoresistance was observed when PDOs were co-cultured with paired CAFs or cultured in a medium containing human GDF15 recombinant protein. Downstream exploration revealed that GDF15 was involved in AKT pathway activation and mitochondrial oxidative phosphorylation in EAC cells. Moreover, GDF15 expression was significantly higher in the tumor tissue than in adjacent normal tissue in EAC patients (p=0.0056). Low GDF15 mRNA expression was associated with better OS in EAC patients (p=0.025). Notably, GDF15 serum concentration was significantly higher after the CROSS treatment (p<0.0001), and a high serum concentration after the CROSS was an independent risk factor for a poor OS in EAC patients (HR: 3.100, 95%CI: 1.092-8.799, p=0.034). Conclusion: NCRT followed by surgery represents the optimal treatment strategy for managing locally advanced EC patients. The co-culture system of EAC PDOs with paired CAFs offers a viable approach for studying tumor-stroma interactions. CAFs play a crucial role in modulating EAC treatment resistance, with GDF15 partly linking CAFs and EAC communications within the tumor microenvironment. GDF15 exhibits a regulatory role in EAC mitochondrial function and therapy resistance. Moreover, the predictive value of GDF15 serum concentration highlights its potential as a prognostic biomarker in EAC patients

Origin of negative electrocaloric effect in Pnma-type antiferroelectric perovskites

Anomalous electrocaloric effect (ECE) with decreasing temperature upon application of an electric field is known to occur in antiferroelectrics (AFEs), and previous understanding refers to the field-induced canting of electric dipoles if there is no phase transitions. Here, we use a first-principle-based method to study the ECE in Nd-substituted BiFeO3 (BNFO) perovskite solid solutions, which has the Pnma-type AFE ground state. We demonstrate another scenario to achieve and explain anomalous ECE, emphasizing that explicit consideration of octahedral tiltings is indispensable for a correct understanding. This mechanism may be general for AFEs for which the antipolar mode is not the primary order parameter. We also find that the negative ECE can reach a large magnitude in BNFO

Linking Cancer Stem Cell Plasticity to Therapeutic Resistance-Mechanism and Novel Therapeutic Strategies in Esophageal Cancer

Esophageal cancer (EC) is an aggressive form of cancer, including squamous cell carcinoma (ESCC) and adenocarcinoma (EAC) as two predominant histological subtypes. Accumulating evidence supports the existence of cancer stem cells (CSCs) able to initiate and maintain EAC or ESCC. In this review, we aim to collect the current evidence on CSCs in esophageal cancer, including the biomarkers/characterization strategies of CSCs, heterogeneity of CSCs, and the key signaling pathways (Wnt/β-catenin, Notch, Hedgehog, YAP, JAK/STAT3) in modulating CSCs during esophageal cancer progression. Exploring the molecular mechanisms of therapy resistance in EC highlights DNA damage response (DDR), metabolic reprogramming, epithelial mesenchymal transition (EMT), and the role of the crosstalk of CSCs and their niche in the tumor progression. According to these molecular findings, potential therapeutic implications of targeting esophageal CSCs may provide novel strategies for the clinical management of esophageal cancer

Synthesis of dominant plastic microfibre prevalence and pollution control feasibility in Chinese freshwater environments

Microplastic pollution of freshwaters is known to be a great concern in China and these pollutants can be discharged into the coastal environment through fluvial processes, posing threats to the global marine ecosystem. This paper reviewed the literature measuring microplastic pollution in the Chinese freshwater environment and found that microfibres dominate other plastic morphologies in more than 65% of samples collected in surface water, sediments and effluents of wastewater treatment plants and domestic sewers. Current potential sources of microfibre pollution are identified including fishery activities, laundry sewage, and waste textiles according to previous research. Recommendations are offered using the circular economy management framework, such as textile waste reuse and recycling systems in China, for improving current control measures for microplastics in freshwaters

Optimal Power Allocation for Channel-Based Physical Layer Authentication in Dual-Hop Wireless Networks

Channel-based physical-layer authentication, which is capable of detecting spoofing attacks in dual-hop wireless networks with low cost and low complexity, attracted a great deal of attention from researchers. In this paper, we explore the likelihood ratio test (LRT) with cascade channel frequency response, which is optimal according to the Neyman&ndash;Pearson theorem. Since it is difficult to derive the theoretical threshold and the probability of detection for LRT, majority voting (MV) algorithm is employed as a trade-off between performance and practicality. We make decisions according to the temporal variations of channel frequency response in independent subcarriers separately, the results of which are used to achieve a hypothesis testing. Then, we analyze the theoretical false alarm rate (FAR) and miss detection rate (MDR) by quantifying the upper bound of their sum. Moreover, we develop the optimal power allocation strategy between the transmitter and the relay by minimizing the derived upper bound with the optimal decision threshold according to the relay-to-receiver channel gain. The proposed power allocation strategy takes advantage of the difference of noise power between the relay and the receiver to jointly adjust the transmit power, so as to improve the authentication performance on condition of fixed total power. Simulation results demonstrate that the proposed power allocation strategy outperforms the equal power allocation in terms of FAR and MDR

GAM-Based Mooring Alignment for SINS Based on An Improved CEEMD Denoising Method

To solve the self-alignment problem of the Strapdown Inertial Navigation System (SINS), a novel adaptive filter based on Complementary Ensemble Empirical Mode Decomposition (CEEMD) is proposed. The Gravitational Apparent Motion (GAM) is used in the coarse alignment, and the problem of obtaining the attitude matrix between the body frame and the navigation frame is attributed to obtaining the matrix between the initial body frame and the current navigation frame using two gravitational apparent motion vectors at different moments. However, the accuracy and time of this alignment method always suffer from the measurement noise of sensors. Thus, a novel adaptive filter based on CEEMD using an l 2 -norm to calculate the similarity measure between the Probability Density Function (PDF) of each Intrinsic Mode Function (IMF) and the original signal is proposed to denoise the measurements of the accelerometer. Furthermore, the advantage of this filter is verified by comparing with other conventional denoising methods, such as PDF-based EMD (EMD-PDF) and the Finite Impulse Response (FIR) digital low-pass filter method. The results of the simulation and experiments indicate that the proposed method performs better than the conventional methods in both alignment time and alignment accuracy

Siliceous mesocellular foam (MCF) supported Cu catalysts for promoting non-thermal plasma activated CO2 hydrogenation towards methanol synthesis

Electrified non-thermal plasma (NTP) catalytic hydrogenation is the promising alternative to the thermal counterparts, being able to be operated under mild conditions and compatible with green electricity/hydrogen. Rational design of the catalysts for such NTP-catalytic systems is one of the keys to improve the process efficiency. Here, we present the development of siliceous mesocellular foam (MCF) supported Cu catalysts for NTP-catalytic CO2 hydrogenation to methanol. The findings show that the pristine MCF support with high specific surface area and large mesopore of 784 m2 g−1 and ~8.5 nm could promote the plasma discharging and the diffusion of species through its framework, outperforming other control porous materials (viz., silicalite-1, SiO2, and SBA-15). Compared to the NTP system employing the bare MCF, the inclusion of Cu and Zn in MCF (i.e., Cu1Zn1/MCF) promoted the methanol formation of the NTP-catalytic system with a higher space-time yield (STY) of methanol at ~275 μmol gcat−1 h−1 and a lower energy consumption of 26.4 kJ mmolCH3OH−1 (conversely, ~225 μmol gcat−1 h−1 and ~71 kJ mmolCH3OH−1, respectively, for the bare MCF system at 10.1 kV). The findings suggest that inclusion of active metal sites (especially Zn species) could stabilize the CO2/CO-related intermediates to facilitate the surface reaction towards methanol formation

A Retrospective Study of 52 Patients With Primary Small Cell Carcinoma of the Esophagus Treated With Radical Surgery

Background: Primary small cell carcinoma of the esophagus (SCCE) is a rare and extremely fatal disease. We aim to evaluate the efficacy of radical surgery for resectable SCCE and to explore potential prognostic factors. Methods: We retrospectively reviewed 52 consecutive SCCE patients who underwent radical surgery from February 1993 to November 2014 at a single institution. The Kaplan-Meier estimator with log-rank test was used to assess overall survival (OS), disease-free survival (DFS) and median survival time. Univariate and multivariable analyses were used to evaluate prognostic factors through Cox proportional hazard regression model. Results: Twenty-five (48.1%) patients were treated with surgery alone, whereas 27 (51.9%) patients underwent adjuvant therapy after surgery. The median OS time was 17.4 months (95% CI: 13.5-21.3). The median DFS time was 13.4 months (95% CI: 7.7-19.0). Patients whose tumors were located in the lower part of thoracic esophagus and the esophagogastric junction showed significantly better OS (27.0 vs. 13.2 months, P = 0.016) and DFS (27.0 vs. 11.3 months, P = 0.017) than those located in the upper and middle parts. Patients with N0 status experienced significantly better OS (21.4 vs. 11.6 months, P = 0.012) and DFS (21.4 vs. 8.6 months, P = 0.012) than those with N+ status. Patients whose tumor lengths were shorter than 5 cm had a better OS (17.4 vs. 5.7 months, P = 0.035) than those longer than 5 cm. Patients who underwent chemotherapy experienced a significantly improved OS (21.0 vs. 14.1 months, P = 0.032) compared to surgery alone. Multivariable analysis showed that lower tumor location, shorter tumor length, pN0 status and chemotherapy independently predicted better OS; lower tumor location and pN0 status independently predicted better DFS. Conclusions: Radical surgery in combination with chemotherapy has better outcomes than surgery alone for resectable SCCE. Higher tumor location, longer tumor length, lymph node metastasis and not undergoing chemotherapy independently predict worse prognoses