Application value of laparoscopic surgery in elderly patients (≥ 75 years) with colorectal cancer and prognostic factors influencing 5-year overall survival.

OBJECTIVE: To investigate the application value of laparoscopic surgery in elderly patients (≥ 75 years) with colorectal cancer, and to identify the prognostic factors influencing the long-term survival in this demographic, and to establish a predictive nomogram model. METHODS: A retrospective analysis was conducted on 146 elderly (≥ 75 years old) colorectal cancer patients who underwent radical surgery in Baoji People's Hospital from August 2016 to February 2018, including 55 patients who underwent laparotomy and 91 patients who underwent laparoscopic surgery. Survival curves were plotted using the Kaplan-Meier method, and differences in prognosis were assessed using the Log-rank test. Prognostic impacts of various factors on 5-year survival were analyzed using a Cox proportional hazards model. Significant predictors identified in the Cox model were used to construct a nomogram for predicting survival, which was then validated for accuracy and clinical utility. RESULTS: Laparoscopic surgery was associated with shorter hospital stays (P = 0.022), although at a higher cost (P = 0.011). The laparoscopic group also had less intraoperative bleeding (P < 0.001), incision length (P < 0.001), time to first postoperative expectoration (P < 0.001), time to first postoperative feeding (P = 0.002), and time to postoperative peritoneal drainage (P = 0.003) compared to the open surgery group. Additionally, the rate of postoperative wound complications was also lower in the laparoscopic group (P = 0.014). There was no significant difference in the 5-year post-treatment survival between the two groups (P = 0.150). Multifactorial Cox regression analysis revealed that a history of diabetes mellitus (P = 0.037), vascular infiltration (P = 0.026), nerve bundle invasion (P = 0.001), and TNM stage (P = 0.001) were independent prognostic factors affecting the 5-year survival of patients with advanced colorectal cancer. The constructed nomogram showed high predictive accuracy for 1-, 3-, and 5-year survival, with AUC values of 0.91, 0.87, and 0.79, respectively. Calibration curves and decision curve analysis confirmed the model's clinical utility. Risk formula: History of diabetes mellitus * -0.696194503 + Vascular infiltration * -0.769736513 + Nerve bundle invasion * -1.1709777 + TNM staging * 1.201933691. CONCLUSION: Laparoscopic surgery can reduce intraoperative trauma and accelerate postoperative recovery in elderly colorectal cancer patients (≥ 75 years) compared to open surgery. The developed nomogram model based on independent prognostic factors such as diabetes history, vascular infiltration, nerve bundle invasion, and TNM staging, facilitates tailored prognostic assessment, enhancing individual patient management.

Bilaterally Aligned Electroosmotic Flow Generated by Porous Microneedle Device for Dual-Mode Delivery.

Here, a novel porous microneedle (PMN) device with bilaterally aligned electroosmotic flow (EOF) enabling controllable dual-mode delivery of molecules is developed. The PMNs placed at anode and cathode compartments are modified with anionic poly-2-acrylamido-2-methyl-1-propanesulfonic acid and cationic poly-(3-acrylamidopropyl) trimethylammonium, respectively. The direction of EOF generated by PMN at the cathode compartment is, therefore, reversed from cathode to anode, countering the unwanted cathodal suctioning of interstitial fluid caused by reverse iontophoresis. With the bilateral alignment of EOF, the versatility of the proposed device is evaluated by delivering molecules with different charges and sizes using Franz cell. In addition, a 3D printed probe device is developed to ease practical handling and minimize electrical stimulation by integrating two PMNs in closed proximity. Finally, the performance of the integrated probe device is demonstrated by dual delivery of a variety of molecules (methylene blue, rhodamine B, and fluorescein isothiocyanate-dextran) using pig skin and vaccination using mice with delivered ovalbumin.

Microfluidic particle counter visualizing mucosal antibodies against SARS-CoV-2 in the upper respiratory tract for rapid evaluation of immune protection.

Mucosal antibodies in the upper respiratory tract are the earliest and most critical responders to prevent respiratory infections, providing an indication for the rapid evaluation of immune protection. Here, we report a microfluidic particle counter that directly visualizes mucosal antibody levels in nasal mucus. The mucosal anti-SARS-CoV-2 spike receptor binding domain (RBD) antibodies in nasal secretions first react with magnetic microparticles (MMPs) and polystyrene microparticles (PMPs) that are surface-modified to form a "MMPs-anti-spike RBD IgG-PMPs" complex when RBD is present. After magnetic separation and loading into the microfluidic particle counter, the free PMPs, which are reduced with increasing anti-spike RBD IgG antibody levels, are trapped by a microfluidic particle dam and accumulate in the trapping channel. A sensitive mode [limit of detection (LOD): 14.0 ng mL-1; sample-to-answer time: 70 min] and an equipment-free rapid mode (LOD: 37.4 ng mL-1; sample-to-answer time: 20 min) were achieved. Eighty-seven nasal secretion (NS) samples from vaccinees were analyzed using our microfluidic particle counter, and the results closely resemble those of the gold-standard enzyme-linked immunosorbent assay (ELISA). The analysis shows that higher antibody levels were found in convalescent volunteers compared to noninfected volunteers. Together, we demonstrate a rapid kit that directly indicates immune status, which can guide vaccine strategy for individuals and the government.

On-Site Melanoma Diagnosis Utilizing a Swellable Microneedle-Assisted Skin Interstitial Fluid Sampling and a Microfluidic Particle Dam for Visual Quantification of S100A1.

Malignant melanoma (MM) is the most aggressive form of skin cancer. The delay in treatment will induce metastasis, resulting in a poor prognosis and even death. Here, a two-step strategy for on-site diagnosis of MM is developed based on the extraction and direct visual quantification of S100A1, a biomarker for melanoma. First, a swellable microneedle is utilized to extract S100A1 in skin interstitial fluid (ISF) with minimal invasion. After elution, antibody-conjugated magnetic microparticles (MMPs) and polystyrene microparticles (PMPs) are introduced. A high expression level of S100A1 gives rise to a robust binding between MMPs and PMPs and reduces the number of free PMPs. By loading the reacted solution into the device with a microfluidic particle dam, the quantity of free PMPs after magnetic separation is displayed with their accumulation length inversely proportional to S100A1 levels. A limit of detection of 18.7 ng mL-1 for S100A1 is achieved. The animal experiment indicates that ISF-based S100A1 quantification using the proposed strategy exhibits a significantly higher sensitivity compared with conventional serum-based detection. In addition, the result is highly comparable with the gold standard enzyme-linked immunosorbent assay based on Lin's concordance correlation coefficient, suggesting the high practicality for routine monitoring of melanoma.

Transdermal drug delivery using a porous microneedle device driven by a hydrogel electroosmotic pump.

Integrating a hydrogel electroosmotic pump with a parylene C-coated porous microneedle (PMN) is developed for transdermal drug delivery applications. The hydrogel pump is fabricated by combining an anionic and a cationic hydrogel to generate enhanced electroosmosis flow (EOF) to drive the transportation of molecules via PMN.

Machine Learning in Unmanned Systems for Chemical Synthesis.

Chemical synthesis is state-of-the-art, and, therefore, it is generally based on chemical intuition or experience of researchers. The upgraded paradigm that incorporates automation technology and machine learning (ML) algorithms has recently been merged into almost every subdiscipline of chemical science, from material discovery to catalyst/reaction design to synthetic route planning, which often takes the form of unmanned systems. The ML algorithms and their application scenarios in unmanned systems for chemical synthesis were presented. The prospects for strengthening the connection between reaction pathway exploration and the existing automatic reaction platform and solutions for improving autonomation through information extraction, robots, computer vision, and intelligent scheduling were proposed.

A Fully Integrated, Ready-to-Use Distance-Based Chemosensor for Visual Quantification of Multiple Heavy Metal Ions.

Point-of-care devices offering quantitative results with simple steps would allow great useability for untrained end-users. Here, we report a ready-to-use chemosensor integrating automatic sample metering, on-chip reaction, gravitational-magnetic separation, and a distance-based readout for visual quantification of multiple heavy metal ions. Deoxyribozymes (DNAzymes), probe-modified magnetic microparticles (MMPs), and polystyrene microparticles (PMPs) are preloaded into a microfluidic chip and freeze-dried. After the water sample is collected with automatic volume metering, the particles are resuspended, and the MMPs and PMPs hybridize with DNAzyme at its two termini, forming the "MMPs-DNAzyme-PMPs" structure. When target metal ions are present, the DNAzymes are cleaved, yielding an increased number of free PMPs. All on-chip reactions are controlled by stopping the liquid flow at capillary valves and bursting it with hand-controlled tilting. Using the chip with a gravitational-magnetic separator, the free PMPs are separated from "MMPs-DNAzyme-PMPs" and accumulate into the trapping channel with a nozzle, forming a visual bar with growing distances proportional to the concentration of target metal ions. The achieved limit of detection (LOD) values for Cu2+ (103.1 nM), Pb2+ (69.5 nM), and Ag+ (793.6 nM) are below the maximum contamination levels. High selectivity of 100-fold, 200-fold, and 20-fold against interference is obtained. Moreover, by integrating three identical channels in parallel, simultaneous detection of the above-mentioned heavy metal ions in fresh and tap water samples is also achieved with high accuracy. Together, this fully integrated and easily operated platform embodies excellent potential for rapid, on-site sensing by unskilled users.

Down-regulation of NOTCH1 and PKM2 can inhibit the growth and metastasis of colorectal cancer cells.

BACKGROUND: Previous studies have revealed the overexpression of Notch receptor 1 (NOTCH1) and pyruvate kinase M2 (PKM2) in colorectal cancer (CRC) tissue and their relationship to disease development. However, whether there is synergy between PKM2 and NOTCH1 needs to be verified. This study aims to analyze the mechanism and relationship between NOTCH1 and PKM2 in CRC. METHODS: Immunohistochemistry was used to measure the expression of NOTCH1 and PKM2 in colorectal cancer, and the correlation between them was analyzed by Pearson test. The protein and mRNA expressions in CRC cell lines were determined by western blot (WB) and real-time quantitative reverse transcription PCR (qRT-PCR). Compound 3K and tangeretin (TGN) were used to inhibit the expressions of PKM2 and NOTCH1, respectively. The wound healing assay and CCK-8 assay were applied to measure the migration and proliferation of cancer cells. RESULTS: Immunohistochemical analysis showed that NOTCH1 and PKM2 were overexpressed in patients with colorectal cancer, and patients with overexpression showed a higher number of lymph node metastases and high tumor stage (III+IV) (P<0.05). In addition, Pearson test showed that the level of NOTCH1 was positively correlated with the level of PKM2 (P<0.05). WB and qRT-PCR showed that the protein and mRNA levels of NOTCH1 and PKM2 in colorectal cancer cells were significantly up-regulated (P<0.05). The inhibition of PKM2 and NOTCH1 had a synergistic effect on reducing the invasion and proliferation of CRC cells. CONCLUSION: NOTCH1 and PKM2 are highly expressed in CRC patients. Inhibiting the expression of NOTCH1 and PKM2 can inhibit the growth and metastasis of CRC cells, providing therapeutic targets for the treatment of CRC.

Microfluidic particle dam for direct visualization of SARS-CoV-2 antibody levels in COVID-19 vaccinees.

Various COVID-19 vaccines are currently deployed, but their immunization varies and decays with time. Antibody level is a potent correlate to immune protection, but its quantitation relies on intensive laboratory techniques. Here, we report a decentralized, instrument-free microfluidic device that directly visualizes SARS-CoV-2 antibody levels. Magnetic microparticles (MMPs) and polystyrene microparticles (PMPs) can bind to SARS-CoV-2 antibodies simultaneously. In a microfluidic chip, this binding reduces the incidence of free PMPs escaping from magnetic separation and shortens PMP accumulation length at a particle dam. This visual quantitative result enables use in either sensitive mode [limit of detection (LOD): 13.3 ng/ml; sample-to-answer time: 70 min] or rapid mode (LOD: 57.8 ng/ml; sample-to-answer time: 20 min) and closely agrees with the gold standard enzyme-linked immunosorbent assay. Trials on 91 vaccinees revealed higher antibody levels in mRNA vaccinees than in inactivated vaccinees and their decay in 45 days, demonstrating the need for point-of-care devices to monitor immune protection.

The Effect of Iodine-125 Radioactive Particle Stent with Doxorubicin-loaded Nano-tetrahedrons Combined with Transarterial Chemoembolization on Survival and Prognosis of Patients with Cholangiocarcinoma.

This study was to analyze the application of doxorubicin-loaded DNA nano-tetrahedral Iodine-125 (I-125) radioactive particle stent (doxorubicin-loaded 125I stent) combined with transarterial chemoembolization (TACE) in improving the prognosis of patients with cholangiocarcinoma (CC). The doxorubicin-loaded DNA nano-tetrahedrons were constructed, the preparation plan was optimized, and the toxicity test was performed. The prepared doxorubicin-loaded DNA nano-tetrahedrons were applied to 85 cases in the K1 group (doxorubicin-loaded 125I + TACE), 85 cases in the K2 group (doxorubicin-loaded 125I), and 85 cases in K3 group (TACE). It was found that the optimal initial concentration of doxorubicin for the preparation of DNA-loaded nano-tetrahedrons was 200 mmol, and the optimal reaction time was 7 hours. The serum total bilirubin (TBIL) level in the K1 group at 30 days after operation was lower than that in the K2 and K3 groups at 7, 14 and 21 days. (P< 0.05). The alkaline phosphatase (ALP) level in the K1 group was lower in contrast to that in the other two groups at 7, 14, and 21 days after surgery (P< 0.05); and the five-year survival rate of patients in the K1 group was greater in contrast to the rate in K2 and K3 groups (P< 0.05). In short, the implantation of a doxorubicin-loaded 125I stent combined with TACE could effectively improve the five-year survival rate of patients with CC and improve the prognosis effect of the patients.

Co-degradation of coexisting pollutants methylparaben (mediators) and amlodipine in enzyme-mediator systems: Insight into the mediating mechanism.

Catalyzed oxidative reactions mediated by enzymes have been proposed as an effective remediation strategy to remove micropollutants. However, enzyme-catalyzed oxidation processes are usually limited to the substrates of phenols and amine compounds. The addition of synthetic redox mediators could extend the types of enzyme-catalyzed substrates. However, the actual applications were hindered by the high cost and potential toxicity of mediators. Here, we discovered a potential HRP-mediator system by exploring the removal of co-existing pollutants amlodipine (AML) and methylparaben (MeP). It was found that MeP served as a redox mediator could efficiently mediate the removal of AML by HRP/H2O2 system. Surface electrostatic potential analysis of AML molecule suggested that MeP radicals (MePOX) could abstract hydrogen from the N-H site on dihydropyridine moiety of AML and then be reduced to MeP. By exploring the mediating effects of substances with MeP-like structure, Hirshfeld charge was used to evaluate the mediating efficiency of mediators. For mediating the degradation of AML, when the Hirshfeld charge of mediator radical was around - 0.3000, the mediating efficiency was the highest. This study improved the HRP-mediated system and provided an efficient and green method for the degradation of co-existing pollutants AML and MeP.

Visual quantitation of silver contamination in fresh water via accumulative length of microparticles in capillary-driven microfluidic devices.

Silver is a heavy metal commonly used as bacteriostatic agents or disinfectants. However, excess amount of silver ion (Ag+) could lead to adverse biological effects on human health. To monitor silver ions in environmental samples, we report a visual quantitative method for analyzing the trace amount of Ag+. A sliver-specific RNA-cleaving DNAzyme Ag10C firstly makes the connection between magnetic microparticles (MMPs) and polystyrene microparticles (PMPs) forming a complex as "MMPs-Ag10C-PMPs". When Ag+ is present, the Ag10C is cleaved, resulting in an increase of free PMPs. By dropping 3 µL of reacted particle solution to a capillary-driven microfluidic chip, MMPs and MMPs-Ag10C-PMPs are removed by a magnetic separator during the flow, while free PMPs can continue flowing until being trapped and accumulating at a particle dam with a narrow nozzle. The accumulation length of PMPs linearly increases with the increment of Ag+ concentrations in the range of 0-10 µM, and readable by the naked eye. We have achieved a limit of detection (LOD) down to 453.7 nM, which is significantly lower than the maximum contaminant level of 926 nM set by World Health Organization (WHO). More importantly, after validating the high selectivity against other metal ions and stable performance in different pH and water hardness, we demonstrate recovery rate >96.8% for tests of multiple fresh water sources, manifesting the feasibility in practical detection in real water samples.

Mn(II)-Mn(III)-Mn(IV) redox cycling inhibits the removal of methylparaben and acetaminophen mediated by horseradish peroxidase: New insights into the mechanism.

Catalyzed oxidative coupling reactions mediated by enzyme have been proposed as an effective remediation strategy to remove micropollutants, however, little is known about how the Mn(II) redox cycling affects the horseradish peroxidase (HRP)-mediated reactions in wastewater treatment. Here, we explored the removal of two pharmaceuticals and personal care products (PPCPs), methylparaben (MeP) and acetaminophen (AAP), in HRP-mediated reaction system with dissolved Mn (II). It was found that the conversion rate of AAP was about 284 times higher than that of MeP, and Mn (II) significantly inhibited HRP-catalyzed MeP removal but had little influence on that of AAP. X-ray photoelectron spectroscopy (XPS) and theoretical calculations demonstrated that HRP converted Mn(II) into Mn(III), and then generated MnO2 colloid, which inhibited the removal of the substrates. Moreover, the results of theoretical calculations also showed that the binding energy between HRP and Mn was 27.68 kcal/mol, which was higher than that of MeP (25.24 kcal/mol) and lower than that of AAP (30.19 kcal/mol). Therefore, when MeP and Mn (II) coexisted in the reaction system, HRP preferentially reacted with Mn(II), which explained the different impacts of Mn (II) on the removal of MeP and AAP. Additionally, Mn (II) significantly altered the product distribution by decreasing the amount of polymerization products. Overall, our work here revealed the roles of Mn (II) in the removal of MeP and AAP mediated by HRP, having strong implications for an accurate assessment of the influence of Mn(II) redox cycling on the removal of PPCPs in wastewater treatment.

Microfluidic particle accumulation for visual quantitation of copper ions.

A portable biosensor has been developed based on microfluidic particle accumulation for visual quantification of copper ions. A copper-dependent DNAzyme is used to connect magnetic microparticles (MMPs) and polystyrene microparticles (PMPs), forming "MMPs-DNAzyme-PMPs." When copper ions are present, the DNAzyme is cleaved, allowing free PMPs to be released from the MMPs-DNAzyme-PMP complex. Using a capillary-flow-based microfluidic device, the MMPs-DNAzyme-PMPs are first separated by a magnetic chamber, allowing the free PMPs to continue flowing until being trapped at a particle dam with a narrowing nozzle. Therefore, as a thermometer-like display, the copper level can be visually quantified by the accumulation length of the free PMPs in the trapping microchannel. The limit of detection (LOD) is 33 nM determined by the linear range of 25-100 nM, which is 900 times lower than the prevalent standard (~30 µM) in Hong Kong. The system shows excellent selectivity (> 1000-folds) against other heavy metal ions and abilities to adapt to multiple water environmental conditions. Tests on tap water samples and three local natural water sources in Hong Kong manifest that the device can effectively monitor the quality of freshwater with >70% recovery and 26.16% RSD.

Portable microfluidic device with thermometer-like display for real-time visual quantitation of Cadmium(II) contamination in drinking water.

Cadmium (Cd2+) is a toxic metal ion widely existing in water, soil and food. Conventional water quality control heavily relies on expensive, bulky and sophisticated instrument such as spectrometry, which is time-consuming and incompatible with on-site, real-time detection. Here, a portable microfluidic device with thermometer-like visual readouts is developed for real-time quantitation of cadmium (II) contamination in drinking water. We use Cd2+-dependent DNAzyme (Cd16), which is cleaved when Cd2+ is present, creating a single strand DNA which triggers catalytic hairpin assembly (CHA) with two hairpins H1 and H2 as the building blocks. Plenty of H1H2 complex, the product after the Cd2+-mediated CHA, are generated, which can connect magnetic microparticles (MMPs) and polystyrene microparticles (PMPs), forming "MMPs-H1H2-PMPs" sandwich structure. To provide visual readout to quantitate the particle connection, the particle solution is loaded into a portable microfluidic chip. A magnetic separator first removes MMPs and the connected PMPs, while free PMPs can continue flowing until accumulating into a bar at the particle dam. Shown as a thermometer-like display, the accumulating length is inversely proportional to the concentration of Cd2+, enabling quantitative detection of Cd2+ by the naked eye. The proposed device exhibits a limit of detection of 11.3 nM of Cd2+, selectivity >200-fold against other metal ions, high tolerance to the interferents present in drinking water and high recovery rate in tap water. With high analytical performance without any sample preparation step, this portable device is highly promising in real-time monitoring in urban drinking water at sites.

Ligand Effects of BrettPhos and RuPhos on Rate-Limiting Steps in Buchwald-Hartwig Amination Reaction Due to the Modulation of Steric Hindrance and Electronic Structure.

The differences in catalytic activity between two catalyst ligands of Buchwald-Hartwig amination reaction, BrettPhos versus RuPhos, were investigated using density functional theory (DFT) calculations. The reaction process consists of three consecutive steps: (1) oxidative addition, (2) deprotonation, and (3) reductive elimination. Among them, the rate-limiting step of Pd-BrettPhos catalytic system is oxidative addition but that of Pd-RuPhos catalytic system is reductive elimination due to their differences in steric hindrance and electronic structure. It was also revealed that amines with large-size substituents or halides with electron-withdrawing groups would reduce the activation energy barriers of the reactions. The insights gained from the calculations of the Buchwald-Hartwig amination reaction would be helpful for the rational designing of new catalysts and reactions.

Microfluidic Particle Dam for Visual and Quantitative Detection of Lead Ions.

Lead contamination in drinking water is a primary concern in public health, but it is difficult to monitor by end-users. Here, we provide a rapid and power-free microfluidic particle dam which enables visual quantification of lead ions (Pb2+) by the naked eye. GR-5 DNAzyme with extended termini can connect magnetic microparticles (MMPs) and polystyrene microparticles (PMPs) by DNA hybridization, forming "MMPs-GR-5-PMPs". When Pb2+ is present, GR-5 is cleaved, resulting in an increasing number of free PMPs. To visually count the free PMPs, the solution is loaded to a capillary-driven microfluidic device that consists of a magnetic separator to remove the MMPs-GR-5-PMPs, followed by a particle dam that traps and accumulates the free PMPs into a visual bar with growing length proportional to the concentration of lead. The device achieved a limit of detection at 2.12 nM (0.44 ppb), high selectivity (>20,000-fold) against other metal ions, high tolerance to different pH and water hardness, and is compatible with tap water with a high recovery rate, enabling visual quantification and user-friendly interface for rapid screening of water safety.