Enhanced dynamic covalent chemistry for the controlled release of small molecules and biologics from a nanofibrous peptide hydrogel platform.

Maintaining safe and potent pharmaceutical drug levels is often challenging. Multidomain peptides (MDPs) assemble into supramolecular hydrogels with a well-defined, highly porous nanostructure that makes them attractive for drug delivery, yet their ability to extend release is typically limited by rapid drug diffusion. To overcome this challenge, we developed self-assembling boronate ester release (SABER) MDPs capable of engaging in dynamic covalent bonding with payloads containing boronic acids (BAs). As examples, we demonstrate that SABER hydrogels can prolong the release of five BA-containing small-molecule drugs as well as BA-modified insulin and antibodies. Pharmacokinetic studies revealed that SABER hydrogels extended the therapeutic effect of ganfeborole from days to weeks, preventing Mycobacterium tuberculosis growth better than repeated oral administration in an infection model. Similarly, SABER hydrogels extended insulin activity, maintaining normoglycemia for six days in diabetic mice after a single injection. These results suggest that SABER hydrogels present broad potential for clinical translation.

Optimizing Performance in Supercapacitors through Surface Decoration of Bismuth Nanosheets.

Bismuth (Bi) exhibits a high theoretical capacity, excellent electrical conductivity properties, and remarkable interlayer spacing, making it an ideal electrode material for supercapacitors. However, during the charge and discharge processes, Bi is prone to volume expansion and pulverization, resulting in a decline in the capacitance. Deposition of a nonmetal on its surface is considered an effective way to modulate its morphology and electronic structure. Herein, we employed the chemical vapor deposition technique to fabricate Se-decorated Bi nanosheets on a nickel foam (NF) substrate. Various characterizations indicated that the deposition of Se on Bi nanosheets regulated their surface morphology and chemical state, while sustaining their pristine phase structure. Electrochemical tests demonstrated that Se-decorated Bi nanosheets exhibited a 51.1% improvement in capacity compared with pristine Bi nanosheets (1313 F/g compared to 869 F/g at a current density of 5 A/g). The energy density of the active material in an assembled asymmetric supercapacitor could reach 151.2 Wh/kg at a power density of 800 W/kg. These findings suggest that Se decoration is a promising strategy to enhance the capacity of the Bi nanosheets.

Building Low-Cost, High-Performance Flexible Photodetector Based on Tetragonal Phase VO2 (A) Nanorod Networks.

We present a straightforward and cost-effective method for the fabrication of flexible photodetectors, utilizing tetragonal phase VO2 (A) nanorod (NR) networks. The devices exhibit exceptional photosensitivity, reproducibility, and stability in ambient conditions. With a 2.0 V bias voltage, the device demonstrates a photocurrent switching gain of 1982% and 282% under irradiation with light at wavelengths of 532 nm and 980 nm, respectively. The devices show a fast photoelectric response with rise times of 1.8 s and 1.9 s and decay times of 1.2 s and 1.7 s for light at wavelengths of 532 nm and 980 nm, respectively. In addition, the device demonstrates exceptional flexibility across large-angle bending and maintains excellent mechanical stability, even after undergoing numerous extreme bending cycles. We discuss the electron transport process within the nanorod networks, and propose a mechanism for the modulation of the barrier height induced by light. These characteristics reveal that the fabricated devices hold the potential to serve as a high-performance flexible photodetector.

Challenges and opportunities in the development of mucosal mRNA vaccines.

mRNA vaccines have played a critical role in controlling the SARS-CoV-2 pandemic, and are being actively studied for use in other diseases. There is a growing interest in applying mRNA vaccines at mucosal surfaces as it enables access to a unique immune reservoir in a less-invasive manner. However, mucosal surfaces present several barriers to mRNA uptake, including degrading enzymes, mucus, and clearance mechanisms. In this mini-review, we discuss our understanding of the immune response to mucosal mRNA vaccines as it compares to systemic mRNA vaccines. We also highlight physical and chemical methods for enhancing mRNA uptake across mucosal tissues. Mucosal mRNA vaccination is a nascent field of research, which will greatly benefit from fundamental investigations into the mechanisms of immune activation and the development of technologies for improved delivery.

Gastrointestinal Delivery of an mRNA Vaccine Using Immunostimulatory Polymeric Nanoparticles.

mRNA vaccines can be translated into protein antigens, in vivo, to effectively induce humoral and cellular immunity against these proteins. While current mRNA vaccines have generated potent immune responses, the need for ultracold storage conditions (- 80 °C) and healthcare professionals to administer the vaccine through the parenteral route has somewhat limited their distribution in rural areas and developing countries. Overcoming these challenges stands to transform future deployment of mRNA vaccines. In this study, we developed an mRNA vaccine that can trigger a systemic immune response through administration via the gastrointestinal (GI) tract and is stable at 4 °C. A library of cationic branched poly(ß-amino ester) (PBAE) polymers was synthesized and characterized, from which a polymer with high intracellular mRNA delivery efficiency and immune stimulation capacity was down-selected. mRNA vaccines made with the lead polymer-elicited cellular and humoral immunity in mice. Furthermore, lyophilization conditions of the formulation were optimized to enable storage under refrigeration. Our results suggest that PBAE nanoparticles are potent mRNA delivery platforms that can elicit B cell and T cell activation, including antigen-specific cellular and humoral responses. This system can serve as an easily administrable, potent oral mRNA vaccine.

Laparoscopic single-layer running "trapezoid-shaped" suture versus mechanical stapling for esophagojejunostomy after total gastrectomy for gastric cancer: cost-effect analysis of propensity score-matched study cohorts.

OBJECTIVES: Totally laparoscopic total gastrectomy has been developed with difficulty in intracorporeal esophagojejunostomy. Although mechanical stapling has been widely used for intracorporeal esophagojejunostomy, manual suture holds great promise with the emergence of high-resolution 3D vision and robotic surgery. After exploration of how to improve the safety and efficiency of intracorporeal suture for esophagojejunostomy, we recommended the technique of single-layer running "trapezoid-shaped" suture. The cost-effectiveness was analyzed by comparing with conventional mechanical stapling. METHODS: The study retrospectively reviewed the patients undergoing laparoscopic gastrectomy for gastric cancer from January 2010 to December 2021. The patients were divided into two cohorts based on the methods of intracorporeal esophagojejunostomy: manual suture versus stapling suture. Propensity score matching was performed to match patients from the two cohorts at a ratio of 1:1. Then group comparison was made to determine whether manual suture was non-inferior to stapling suture in terms of operation time, anastomotic complications, postoperative hospital stay, and surgical cost. RESULTS: The study included 582 patients with laparoscopic total gastrectomy. The manual and stapling suture for esophagojejunostomy were performed in 50 and 532 patients, respectively. In manual suture cohort, the median time for the whole operation and digestive tract reconstruction were 300 min and 110 min. There was no anastomotic bleeding and stenosis but two cases of anastomotic leak which occurred at 3 days after surgery. The median length of postoperative hospital stay was 11 days. After propensity score matching, group comparison yielded two variables with statistical significance: time for digestive tract reconstruction and surgery cost. The manual suture cohort spent less money but more time for esophagojejunostomy. Intriguingly, the learning curve of manual suture revealed that the time for digestive tract reconstruction was declined with accumulated number of operations. CONCLUSIONS: Laparoscopic single-layer running "trapezoid-shaped" suture appears safe and cost-effective for intracorporeal esophagojejunostomy after total gastrectomy. Although the concern remains about prolonged operation time for beginners of performing the suture method, adequate practice is expected to shorten the operation time based on our learning curve analysis.

Degradation of diclofenac via sequential reduction-oxidation by Ru/Fe modified biocathode dual-chamber bioelectrochemical system: Performance, pathways and degradation mechanisms.

A sequential reduction-oxidation for DCF degradation was proposed by alternating anaerobic/aerobic conditions at Ru/Fe-biocathode in a dual-chamber bioelectrochemical system (BES). Results showed that Ru/Fe-electrode was successfully fabricated by in-situ electro-deposition, which was rough and uniformly distributed with Ru0 and Fe0 particles. The morphologic changing and biocompatibility were favorable to increase the surface area and enhance microbial adhesion on Ru/Fe-electrode. At an applied voltage of 0.6 V, the potential and impedance of Ru/Fe-biocathode were -0.80 V and 26 Ω, respectively, lower than that of carbon-felt-biocathode. It led to a higher DCF degradation efficiency of 93.2% under anaerobic conditions, which was superior to that of 88.0% under aerobic conditions. Using NaHCO3 as carbon source, DCF removal efficiency increased with increasing applied voltage, but decreased with increasing initial DCF concentration. Thirteen intermediates were measured, and two degradation pathways were proposed, among which sequential reduction-oxidation of DCF was the main pathway, dechlorination intermediates were first generated by [H] attacked under anaerobic conditions, further oxidized by microbes and OH attacked under aerobic conditions, achieving 69.6% of mineralization. After 4 d of reaction, microcystis aeruginosa growth inhibition rate decreased from 22.9 to 8.0%, signifying a significant reduction in biotoxicity. Bacteria (e.g. Nitrobacter, Nitrosomonas, Pseudofulvimonas, Aquamicrobium, Sulfurvermis, Lentimicrobiaceae, Anaerobineaceae, Bacteroidales, Hydrogenedensaceae, Dethiosulfatibacter and Azoarcus) for DCF degradation were enriched in Ru/Fe-biocathode. Microbes in Ru/Fe-biocathode had established defense mechanisms to acclimate to the unfriendly environment, while Ru/Fe-biocathode possessed higher nitrification and denitrification activities than carbon-felt-biocathode, and Ru/Fe-biocathode might be of aerobic and anaerobic biodegradation activities. DCF could be mineralized by the synergistic reaction between Ru/Fe and bacteria under sequential anaerobic/aerobic conditions.

Simultaneous mineralization of 2-anilinophenylacetate and denitrification by Ru/Fe modified biocathode double-chamber microbial fuel cell.

A double-chamber microbial fuel cell (MFC) with Ru/Fe-modified-biocathode was constructed for simultaneous mineralization of 2-anilinophenylacetate (APA) and denitrification. The factors on performance of simultaneous APA degradation and denitrification were explored. The contributions of ROS to APA degradation were evaluated by EPR and quenching experiments. The microbial community of Ru/Fe-modified-biocathode was determined by high-throughput sequencing. Results showed that low resistance accelerated APA degradation by Ru/Fe-modified-biocathode, while higher initial APA concentration inhibited microbial activity of the biocathode. The optimum ammonia concentration was 50 mg L-1, while too high or too low ammonia concentration did not favor APA degradation. The APA degradation efficiency of Ru/Fe-modified-biocathode-MFC was higher than that of other modified-cathode-MFCs. The APA degradation process confirmed to the pseudo-first-order kinetic model, and APA degradation kinetic constant, the maximum removal efficiency of TOC, ammonia and TN were 2.15d-1, 59.70%, 99.20% and 44.56% respectively, signifying a simultaneous APA mineralization and denitrification performance of Ru/Fe-modified-biocathode-MFC. The coulombic efficiency decreased with APA concentration increase. OH was the primary radical in APA degradation progress. Eight kinds of intermediates were measured, and two APA degradation pathways were proposed, among which APA hydroxylation was the main pathway. The microbial community of Ru/Fe-modified-biocathode was dominated with Nitrosomonas at genus level, and enriched with various APA-degraders, nitrifiers, and denitrifiers such as Pseudomonas, Nitrospira, Nitrobacter, Paracoccus, Thermomonas, Dechloromonas, and Clostridium_Sutra_stricto_1. COG analysis showed the redox reaction of Ru/Fe might affect signal transduction and environment adaptation, while FAPROTAX analysis suggested that Ru/Fe-modified-biocathode exhibited higher nitrification activity than that of carbon-felt-biocathode. The synergistic mechanism of simultaneous APA mineralization and denitrification was mainly redox reaction of Ru/Fe and supplemented by aerobic biodegradation.

Can Elevated Pretreatment Serum Carcinoembryonic Antigen Levels Serve as a Potential Biomarker Guiding Adjuvant Chemotherapy in Rectal Cancer Patients With ypTis-3N0 After Neoadjuvant Radiotherapy and Surgery?

Survival benefit of adjuvant chemotherapy (ACT) remained controversial in patients with stage II/III rectal cancer (RC) who received neoadjuvant therapy and surgery. This study aimed to investigate the guiding role of elevated pretreatment serum carcinoembryonic antigen (CEA) levels for receiving ACT in yield pathological Tis-3N0 (ypTis-3N0) RC patients after neoadjuvant radiotherapy and surgery. Between 2004 and 2015, 10,973 RC patients with ypTis-3N0 who received neoadjuvant radiotherapy and radical surgery were retrospectively analyzed using the Surveillance, Epidemiology, and End Results (SEER) database. Compared with CEA-normal group, elevated-CEA patients had worse 5-year CSS rate (90.1 vs 83.5%). The 5-year CSS rates were 86.3 and 87.4% for ypTis-3N0M0 patients with or without ACT, respectively. Patients receiving ACT had a comparable 5-year CSS rate compared to those who did not regardless of CEA levels in ypTis-3N0M0 RC patients (CEA elevation group: 76.4 vs. 83.5%, P = 0.305; CEA normal group: 90.0 vs. 90.1%, P = 0.943). Intriguingly, ypT3N0M0 RC patients with elevated CEA levels may benefit from ACT (5-year CSS: 69.1 vs. 82.9%, P = 0.045), while those with normal CEA levels did not (5-year CSS: 89.3 vs. 89.3%, P = 0.885). Multivariate Cox analysis demonstrated that ACT tended to be a protective factor in elevated-CEA ypT3N0M0 RC patients (HR = 0.633, 95% CI = 0.344-1.164, P = 0.141), while ACT was not associated with improved CSS in normal-CEA ypT3N0M0 RC patients (HR = 1.035, 95% CI = 0.487-2.202, P = 0.928). Elevated pretreatment serum CEA levels may serve as a promising biomarker guiding ACT in rectal cancer patients with ypT3N0M0.

Identification of a novel pathogenic MLH1 mutation and recommended genetic screening strategy: An investigation of three Chinese Lynch syndrome pedigrees.

BACKGROUND: Lynch syndrome (LS) is an autosomal-dominant disorder that increases the risk of many cancers. The genetic basis of LS is germline mutations in DNA mismatch repair genes. METHODS: We performed next-generation sequencing on blood cells obtained from the members of three unrelated LS pedigrees. Immunohistochemistry staining was performed to analyze protein expression. RESULTS: Multigene panel screening revealed three mutL homolog 1 (MLH1) pathogenic mutations (c.199G>A, c.790 + 1G>A, and c.1557_1558 + 8delGGGTACGTAA, unreported) confirmed by Sanger sequencing. Immunohistochemistry showed a loss of MLH1 protein expression. We also confirmed that the unreported mutant allele was inherited for at least three generations. CONCLUSION: These results provide new insights into the molecular mechanisms underlying the pathogenicity of MLH1 mutations and reaffirm the importance of genetic screening for the early diagnosis of LS.

Clinicopathological Characteristics and Prognosis of cT1N0M1 Gastric Cancer: A Population-Based Study.

BACKGROUND: Distant metastasis of early gastric cancer is a rare subgroup and poorly understood. The present study is aimed at summarizing the clinicopathological characteristics, prognosis, and management of clinical T1N0M1 (cT1N0M1) gastric cancer. METHOD: Between 2004 and 2015, patients diagnosed with cT1N0M1 gastric cancer were retrospectively analyzed using the Surveillance, Epidemiology, and End Results (SEER) database. RESULTS: A total of 1093 cT1N0M1 gastric cancer patients were identified. 49 patients (4.5%) received cancer-directed surgery, and 113 patients (10.4%) were managed with radiotherapy. Compared with the other stage IV diseases, a relatively high proportion of black population (19.9% vs. 15.8%), patients older than 60 years (63.1% vs. 57.8%), and adenocarcinoma (59.5% vs. 55.9%) were observed in the cT1N0M1 gastric cancer subgroup. Besides that, patients with cT1N0M1 had the characteristics of less poor differentiated or undifferentiated (54.3% vs. 61.7%). Patients with cT1N0M1 had worse cancer-specific survival (CSS) and overall survival (OS) as compared to the other metastatic gastric cancer patients (CSS: p = 0.002, OS: p = 0.001 for log-rank test). Intriguingly, patients with cT1N0M1 had poor prognosis as compared to patients with cT1N+M1 (CSS: p = 0.015, OS: p = 0.007 for log-rank test). The 3-year and 5-year CSS for patients with cT1N0M1 were 5.7% and 4.0%, respectively. The addition of surgery resulted in improved CSS (p < 0.001 for log-rank test) while radiotherapy was not associated with CSS (p = 0.756 for log-rank test) in patients with cT1N0M1. A multivariate Cox analysis showed that surgery (HR = 0.378, 95% CI: 0.255-0.562) and patients younger than 60 (HR = 0.745, 95% CI: 0.647-0.858) years were independent protective factors for these subgroup patients. CONCLUSION: Patients with cT1N0M1 gastric cancer had distinctive clinicopathological characteristics and presented poor prognosis. Knowledge of these differences contributes to guiding clinical evaluation for metastatic gastric cancer patients. More aggressive therapeutic strategy should be highlighted for this subgroup.

Modularized laparoscopic regional en bloc mesogastrium excision (rEME) based on membrane anatomy for distal gastric cancer.

BACKGROUND: The purpose of the study was to evaluate the safety and feasibility of a new surgical procedure named modularized laparoscopic regional En bloc mesogastrium excision (rEME) based on the membrane anatomy in distal laparoscopic radical gastrectomy for gastric cancer. METHODS: From January 2014 to June 2017, 92 consecutive cases of patients with stages I-III distal gastric cancer were divided into 2 groups: laparoscopic radical gastrectomy plus standard D2 lymph node dissection (SD group, n = 44) and modularized rEME (rEME group, n = 48). Evaluations were made in terms of the operative data, pathological results, recovery time of digestive tract functions, complications, and length of stay. RESULTS: 85 patients (SD group, n = 40 and rEME group, n = 45) were finally included for analysis. There were no significant differences in the median total numbers of dissected LNs (31.98 ± 10.48 vs. 34.93 ± 13.12, p = 0.261), LNs in the greater curvature (12.18 ± 6.55 vs. 13.62 ± 8.09, p = 0.444), LNs in the lesser curvature (19.55 ± 7.40 vs. 17.98 ± 8.31, p = 0.365) between the SD and rEME groups. The rEME group showed lower loss of blood volume (107.11 ± 60.13 ml vs. 146.25 ± 85.78 ml, p = 0.019). No significant differences were found in recovery time of digestive tract functions, postoperative complication rates and length of hospital stay between the two groups. CONCLUSION: Laparoscopic radical gastrectomy plus modularized rEME based on the membrane anatomy is a safe and feasible procedure for distal gastric cancer.