Magnetic hypercrosslinked polymer microspheres for the detection, spatial distribution, source identification and potential risks assessment of five polycyclic aromatic hydrocarbons in city river of plateau lake, Southwest China.

Polycyclic aromatic hydrocarbons (PAHs) have long been globally distributed, and almost worldwide people are exposed to varying degrees of PAHs. Aqueous medium is an important transmission route of PAHs, but the detection of PAHs in aqueous environment has been a challenge. Herein, a magnetic hypercrosslinked polymer microsphere (Fe3O4@SiO2-PS@HCP) was developed for the effective detection of PAHs. Under the effect of multiple factors (hydrophilicity, intermolecular force and molecular volume), Fe3O4@SiO2-PS@HCP shows excellent performance on the enrichment of five PAHs in aqueous environment. Fe3O4@SiO2-PS@HCP was used to capture PAHs in city river of plateau lake. In-depth data analysis showed that factory activities and traffic emissions are the main pollution sources of PAHs. Ecological, carcinogenic and non-carcinogenic risks are almost within the safe range. The carcinogenic and non-carcinogenic risks of PAHs in children are higher than adults, which needs to be taken seriously. This method breaks the dilemma that it is difficult to enrich weakly hydrophilic pollutants in aqueous media, and complements important pathways for tracing sources of pollutants and assessing associated risks. It brings methodological enlightenment into the development of environmental pollution and human health risk assessment methodology.

Highly Efficient Electrosynthesis of Glycine over an Atomically Dispersed Iron Catalyst.

Glycine is a nonessential amino acid that plays a vital role in various biological activities. However, the conventional synthesis of glycine requires sophisticated procedures or toxic feedstocks. Herein, we report an electrochemical pathway for glycine synthesis via the reductive coupling of oxalic acid and nitrate or nitrogen oxides over atomically dispersed Fe-N-C catalysts. A glycine selectivity of 70.7% is achieved over Fe-N-C-700 at -1.0 V versus RHE. Synergy between the FeN3C structure and pyrrolic nitrogen in Fe-N-C-700 facilitates the reduction of oxalic acid to glyoxylic acid, which is crucial for producing glyoxylic acid oxime and glycine, and the FeN3C structure could reduce the energy barrier of *HOOCCH2NH2 intermediate formation thus accelerating the glyoxylic acid oxime conversion to glycine. This new synthesis approach for value-added chemicals using simple carbon and nitrogen sources could provide sustainable routes for organonitrogen compound production.

Alkyl sulfonate surfactant mediates electroreduction of carbon dioxide to ethylene or ethanol over hydroxide-derived copper catalysts.

For CO2 electroreduction (CO2ER) to C2 compounds, it is generally accepted that the formation of ethylene and ethanol shares the same intermediate, *HCCOH. The majority of studies have achieved high faradaic efficiency (FE) towards ethylene, but faced challenges to get high ethanol FE. Herein, we present an alkyl sulfonate surfactant (e.g., sodium dodecyl sulfonate, SDS) mediated CO2ER to a C2 product over an in situ generated Cu catalyst (Cu@SDS) from SDS-modified Cu(OH)2. It achieves the CO2ER to ethylene as the sole C2 product at low applied voltages with a FE of 55% at -0.6 V vs. RHE and to ethanol as the main product at potentials ≥0.7 V with a maximum FE of 64% and a total C2 FE of 86% at -0.8 V, with a current density of 231 mA cm-2 in a flow cell. Mechanism investigation indicates that SDS modifies the oxidation state of the in situ formed Cu species in Cu@SDS, thus tuning the catalyst activity for CO2ER and lowering the C-C coupling energy barrier; meanwhile, it tunes the adsorption mode of the *HCCOH intermediates on the catalyst, thus mediating the selectivity of CO2ER towards C2 products.

Cost-effective prognostic evaluation of breast cancer: using a STAR nomogram model based on routine blood tests.

Background: Breast cancer (BC) is the most common and prominent deadly disease among women. Predicting BC survival mainly relies on TNM staging, molecular profiling and imaging, hampered by subjectivity and expenses. This study aimed to establish an economical and reliable model using the most common preoperative routine blood tests (RT) data for survival and surveillance strategy management. Methods: We examined 2863 BC patients, dividing them into training and validation cohorts (7:3). We collected demographic features, pathomics characteristics and preoperative 24-item RT data. BC risk factors were identified through Cox regression, and a predictive nomogram was established. Its performance was assessed using C-index, area under curves (AUC), calibration curve and decision curve analysis. Kaplan-Meier curves stratified patients into different risk groups. We further compared the STAR model (utilizing HE and RT methodologies) with alternative nomograms grounded in molecular profiling (employing second-generation short-read sequencing methodologies) and imaging (utilizing PET-CT methodologies). Results: The STAR nomogram, incorporating subtype, TNM stage, age and preoperative RT data (LYM, LYM%, EOSO%, RDW-SD, P-LCR), achieved a C-index of 0.828 in the training cohort and impressive AUCs (0.847, 0.823 and 0.780) for 3-, 5- and 7-year OS rates, outperforming other nomograms. The validation cohort showed similar impressive results. The nomogram calculates a patient's total score by assigning values to each risk factor, higher scores indicating a poor prognosis. STAR promises potential cost savings by enabling less intensive surveillance in around 90% of BC patients. Compared to nomograms based on molecular profiling and imaging, STAR presents a more cost-effective, with potential savings of approximately $700-800 per breast cancer patient. Conclusion: Combining appropriate RT parameters, STAR nomogram could help in the detection of patient anemia, coagulation function, inflammation and immune status. Practical implementation of the STAR nomogram in a clinical setting is feasible, and its potential clinical impact lies in its ability to provide an early, economical and reliable tool for survival prediction and surveillance strategy management. However, our model still has limitations and requires external data validation. In subsequent studies, we plan to mitigate the potential impact on model robustness by further updating and adjusting the data and model.

Perioperative toripalimab and chemotherapy in locally advanced gastric or gastro-esophageal junction cancer: a randomized phase 2 trial.

Perioperative chemotherapy is the standard treatment for locally advanced gastric or gastro-esophageal junction cancer, and the addition of programmed cell death 1 (PD-1) inhibitor is under investigation. In this randomized, open-label, phase 2 study (NEOSUMMIT-01), patients with resectable gastric or gastro-esophageal junction cancer clinically staged as cT3-4aN + M0 were randomized (1:1) to receive either three preoperative and five postoperative 3-week cycles of SOX/XELOX (chemotherapy group, n = 54) or PD-1 inhibitor toripalimab plus SOX/XELOX, followed by toripalimab monotherapy for up to 6 months (toripalimab plus chemotherapy group, n = 54). The primary endpoint was pathological complete response or near-complete response rate (tumor regression grade (TRG) 0/1). The results showed that patients in the toripalimab plus chemotherapy group achieved a higher proportion of TRG 0/1 than those in the chemotherapy group (44.4% (24 of 54, 95% confidence interval (CI): 30.9%-58.6%) versus 20.4% (11 of 54, 95% CI: 10.6%-33.5%)), and the risk difference of TRG 0/1 between toripalimab plus chemotherapy group and chemotherapy group was 22.7% (95% CI: 5.8%-39.6%; P = 0.009), meeting a prespecified endpoint. In addition, a higher pathological complete response rate (ypT0N0) was observed in the toripalimab plus chemotherapy group (22.2% (12 of 54, 95% CI: 12.0%-35.6%) versus 7.4% (4 of 54, 95% CI: 2.1%-17.9%); P = 0.030), and surgical morbidity (11.8% in the toripalimab plus chemotherapy group versus 13.5% in the chemotherapy group) and mortality (1.9% versus 0%), and treatment-related grade 3-4 adverse events (35.2% versus 29.6%) were comparable between the treatment groups. In conclusion, the addition of toripalimab to chemotherapy significantly increased the proportion of patients achieving TRG 0/1 compared to chemotherapy alone and showed a manageable safety profile. ClinicalTrials.gov registration: NCT04250948 .

Endoscopic retrograde cholangiopancreatography for diagnosing and treating pediatric biliary and pancreatic diseases.

BACKGROUND: This study evaluated the safety and effectiveness of endoscopic retrograde cholangiopancreatography (ERCP) in pediatric patients with biliary and pancreatic diseases. A retrospective analysis was conducted on 57 ERCP procedures performed in 41 children, primarily for treating pancreatic diseases. The overall success rate was 91.2%, with no major complications observed. Post-ERCP pancreatitis (PEP) occurred in 8.8% of cases. Follow-up examinations over one year showed no recurrence of biliary or pancreatic diseases. Notably, endoscopic treatment led to a significant increase in body mass index (BMI). These findings demonstrate the valuable role of ERCP in managing such conditions. AIM: To evaluate the safety and efficacy of ERCP for the management of biliary and pancreatic diseases in pediatric patients. METHODS: We conducted a retrospective analysis of data from children aged 1-18 years who underwent ERCP for biliary and pancreatic diseases at Beijing Children's Hospital between January 2021 and December 2022. The collected data included procedure time, endoscopic treatment, success rate, and postoperative complications. RESULTS: Forty-one children underwent 57 ERCP procedures, including 14 with biliary duct disease and 27 with pancreatic disease. The mean age of the patients was 7.48 ± 3.48 years. Biliary duct-related treatments were performed 18 times, and pancreatic disease treatments were performed 39 times. ERCP was primarily used to treat pediatric pancreatic diseases [68.4% (39/57) of the procedures]. The overall success rate was 91.2% (52/57 patients). PEP was noted in five patients (8.8%, 5/57), and no instances of bleeding, perforation, or cholangitis were observed. The patients were followed up for over one year, and no recurrence of biliary or pancreatic diseases was detected. Importantly, BMI significantly increased after endoscopic treatment compared to that before treatment (P = 0.001). CONCLUSION: The high success rate and lack of major complications support the valuable role of ERCP in the management of pediatric biliary and pancreatic diseases in the pediatric population.

Effect of skinfold thickness on arm venous access port in cancer patients.

BACKGROUND: Currently, skinfold thickness in studies on arm venous access ports and the effect of venous access port application are unknown. MATERIALS AND METHODS: A total of 256 cancer patients who underwent primary venous access port placement in the Fourth Hospital of Hebei Medical University from September 2022 to March 2023 were selected as the study subjects. Two hundred fifty-six patients were divided into normal skinfold thickness group and high skinfold thickness group according to skinfold thickness. The success rate of primary catheterization of arm venous port catheterization, catheterization operation time, catheterization length and incidence rate of adverse reactions were compared. RESULTS: There was no significant difference in the basic data between the two groups. There was no significant difference in the success rate of primary catheterization between the two groups (p > 0.05), the catheterization operation time in the normal skinfold thickness group was significantly lower than that in the high skinfold thickness group (p < 0.05), the total length of the implanted catheter in the normal skinfold thickness group was significantly lower than that in the high skinfold thickness group (p < 0.05), and the incidence of adverse reactions in the normal skinfold thickness group was significantly lower than that in the high skinfold thickness group (p < 0.05). CONCLUSION: In cancer patients, skinfold thickness can significantly affect the application effect of arm venous port, and normal skinfold thickness for arm venous port has shorter operation time, total length of implanted catheter and lower incidence of adverse reactions.

Re-irradiation for recurrent cervical cancer: A single institutional experience.

Purpose: Salvage treatment of recurrent cervical cancer of patients with a history of radiotherapy is currently a major clinical challenge. The purpose of our study was to retrospectively analyze clinical outcomes of radiation in patients with recurrent cancer who have previously received radiotherapy at our hospital and further explore the efficacy and safety of this treatment modality. Methods: All consecutive patients who underwent re-irradiation were included in our department between January 2015 and December 2017. All the patients received Volumetric Modulated Arc Therapy (VMAT) alone or VMAT followed by three dimensional-image-guided brachytherapy (3D-IGBT). The volume and dose for re-irradiation depended on previous radiation fields, dosimetry and recurrence sites. All patients received systemic chemotherapy before or after re-irradiation. Results: Fifty patients were included in our study. The median time from primary radiotherapy to re-irradiation was 12 months. Local recurrence, which was the most common failure following primary treatment, was present in 25 patients (50.0 %) while regional recurrence, loco-regional recurrence and distant recurrence combined in-filed recurrence was present in 8 (16.0 %), 9 (18.0 %) and 8 patients (16.0 %). Re-irradiation dose to lymph nodes was 45 Gy with or without a boost up to 55-60 Gy, and to the gross mass was 36-45 Gy with or without a boost up to 45-61 Gy. The median follow-up period was 22 (range,4-59) months. The 3-year local control (LC), progression-free survival (PFS), and overall survival (OS) rates were 58.0, 38.7, and 44.4 %, respectively. The median time of PFS and OS was 14 and 26 months, respectively. The interval between two successive radiotherapies beyond 12 months was significantly associated with better LC and PFS (p ≤ 0.05), but without the benefit of OS (p > 0.05). Serum SCC antigen level less than 1.5 ng/ml had a significantly better impact on PFS (p ≤ 0.05). Overall, 14 patients (28 %) experienced ≥ grade 3 acute toxicities, while 9 (18 %) experienced ≥ grade 3 late toxicities. Conclusions: Re-irradiation with VMAT is an effective and safe salvage treatment option with a reasonably good clinical outcome and toxicity profile in selected patients. In our experience, recurrent cancer patients with an interval between two successive radiotherapy courses beyond 12 months and with a serum SCC-Ag level less than 1.5 ng/ml, had improved outcomes.

Post-imprinting modification of molecularly imprinted polymer for proteins detection: A review.

Inspired by protein post-translational modification (PTM), post-imprinting modification (PIM) has been proposed and developed to prepare novel molecularly imprinted polymers (MIPs), which are similar to functionalized biosynthetic proteins. The PIM involves site-directed modifications in the imprinted cavity of the MIP, such as introducing high-affinity binding sites and introducing fluorescent signal molecules. This modification makes the MIP further functionalized and improves the shortcomings of general molecular imprinting, such as single function, low selectivity, low sensitivity, and inability to fully restore the complex function of natural antibodies. This paper describes the characteristics of PIM strategies, reviews the latest research progress in the recognition and detection of protein biomarkers such as lysozyme, prostate-specific antigen, alpha-fetoprotein, human serum albumin, and peptides, and further discusses the importance, main challenges, and development prospects of PIM. The PIM technology has the potential to develop a new generation of biomimetic recognition materials beyond natural antibodies. It can be used in bioanalysis and other multitudinous fields for its unique features in molecule recognition.

The association of serum IL-33/ST2 expression with hepatocellular carcinoma.

BACKGROUND: IL-33 is a multifunctional cytokine with dual functions. However, the clinicopathological and prognostic significance of IL-33 in cancer patients, especially in patients with hepatocellular carcinoma (HCC), remains controversial. Therefore, we conducted a study of 565 patients with HCC and 561 healthy controls and performed a meta-analysis to quantitatively evaluate the above problems. METHODS: We collected blood from 565 patients with HCC and 561 healthy controls. ELISA was used to detect the concentrations of IL-33 and ST2 in the serum, and RT‒PCR was used to detect the levels of IL-33 and ST2 mRNA. Meanwhile, we collected comprehensive literature on IL-33 and the clinical characteristics of cancer patients retrieved from the PubMed, Web of Science and CNKI databases as of December 2022. An odds ratio (OR) with a 95% confidence interval (CI) was used to estimate the impact through overall and stratified analyses. RESULTS: Compared with the healthy control group, the levels of ST2 mRNA and serum in the peripheral blood of HCC patients increased (p < 0.05), while the levels of IL-33 mRNA and serum showed no significant difference between the two groups (p > 0.05). In the meta-analysis section, at the tissue level, the overall analysis showed that the expression of IL-33 was positively correlated with tumor stage, histological grade, distant metastasis, and tumor size. Compared with patients with low IL-33 expression, the 3-year overall survival (OS) rate (OR = 3.467, p < 0.001) and 5-year OS rate (OR = 2.784, p < 0.001) of patients with high IL-33 expression were lower. At the serum expression level, the overall analysis showed that the expression of IL-33 increased the risk of cancer, and the serum level of IL-33 was positively correlated with tumor stage and vascular invasion. CONCLUSION: IL-33/ST2 is a useful predictive or prognostic biomarker in clinical evaluation and may be used as a potential therapeutic target, but much research is needed to verify this hypothesis.

Engineering green MOF-based superhydrophobic sponge for efficiently synchronous removal of microplastics and pesticides from high-salinity water.

Microplastics (MPs) and pesticides are becoming an intractable environmental issue due to their wide spreading and non-degradable nature, posing serious threat to ecosystem and human health. To settle such dilemma, this work reasonably designed a superhydrophobic MOF-based coated sponge (ODSOSS/TiO2/Ni-MOF/PDA@Sponge) through the combination of an environmentally friendly in-situ supersaturated coprecipitation and polysesiloxane modification method. Among them, (I) the introduction of polydopamine (PDA) not only improves the adhesion between coatings and sponge, but also enhances the growth of MOF structure through complexation. (II) The obtained Ni-MOF shows large-area microscale anthemy structure with multilayered flaky texture, forming heterogeneously hierarchical structure with the deposited TiO2 nanoparticles, which promotes photodegradation ability of TiO2 owing to great specific surface area of Ni-MOF. (III) The high specific large area Ni-MOF supplies sufficient action sites for linkage of PDA and polysesiloxane molecules with unique nanocage-like structure, thus further greatly increasing adsorption force for various pollutants. (IV) The superhydrophobicity protect the porous channels of MOF from contamination of various absorbed pollutants, while TiO2 nanoparticles effectively photodegrade the absorbed organic pollutants, endowing the sponge superior recyclability. The superhydrophobic sponge selectively rapidly and synchronously adsorbs various MPs (maintained almost 100% after 60 cycles) and pesticides (adsorption rates 71.6%-95.1%) from high-salinity water. The large-area sponge (9 cm × 6 cm × 1 cm) simultaneously removes almost 100% MPs (40 mg/L), Sudan Ⅲ (10 mg/L), kerosene (30 mL/L), and four pesticides (10 mg/L) within 1 min. Particularly, four pesticides are quickly photocatalytic degraded by the coated sponge. The free radical capture trials show that hydroxyl radicals (·OH) are the main active species of pesticide degradation. Furthermore, we reveal the negative centers where pesticide molecules are most vulnerable to ·OH attack, on basis of the charge distribution and molecular electrostatic potential (MEP) analysis. The adsorption mechanisms are carefully clarified through theoretical calculation and experimental data. This work not only provide an effective superhydrophobic candidate for MPs and pesticides removal in a broad applicable scope (especially in high-salinity wastewater), but also opens a new strategy for environmental remediation.

Construction of 3D copper-chitosan-gas diffusion layer electrode for highly efficient CO2 electrolysis to C2+ alcohols.

High-rate electrolysis of CO2 to C2+ alcohols is of particular interest, but the performance remains far from the desired values to be economically feasible. Coupling gas diffusion electrode (GDE) and 3D nanostructured catalysts may improve the efficiency in a flow cell of CO2 electrolysis. Herein, we propose a route to prepare 3D Cu-chitosan (CS)-GDL electrode. The CS acts as a "transition layer" between Cu catalyst and the GDL. The highly interconnected network induces growth of 3D Cu film, and the as-prepared integrated structure facilitates rapid electrons transport and mitigates mass diffusion limitations in the electrolysis. At optimum conditions, the C2+ Faradaic efficiency (FE) can reach 88.2% with a current density (geometrically normalized) as high as 900 mA cm-2 at the potential of -0.87 V vs. reversible hydrogen electrode (RHE), of which the C2+ alcohols selectivity is 51.4% with a partial current density of 462.6 mA cm-2, which is very efficient for C2+ alcohols production. Experimental and theoretical study indicates that CS induces growth of 3D hexagonal prismatic Cu microrods with abundant Cu (111)/Cu (200) crystal faces, which are favorable for the alcohol pathway. Our work represents a novel example to design efficient GDEs for electrocatalytic CO2 reduction (CO2RR).

A molecularly imprinted fiber array solid-phase microextraction strategy for simultaneous detection of multiple estrogens.

A kind of selective enrichment material based on a homemade molecularly imprinted polymer (MIP) fiber array with high adsorption capacity was developed for the accurate analysis of estrogens in food samples. Here, the MIP with 17ß-estradiol as the template was obtained by in situ polymerization. The chemical composition, morphologies, surface area, and pore size of the polymer were characterized by Fourier transform infrared spectroscopy, scanning electron microscopy, and Brunauer-Emmett-Teller theory. The extraction time, desorption solvent, desorption time, ionic strength, and the pH of solution were investigated to ascertain the best extraction conditions. Under the optimal extraction conditions, three fiber coatings of 17ß-estradiol MIP and commercial polyacrylate (PA) were bound to a homemade handle to assemble the fiber array, respectively. The findings showed that the three-fiber array of the MIP significantly improved the extraction capacity by 145 times compared to PA. The MIP fiber array showed high adsorption capacity for the template molecule 17ß-estradiol and its structural analogues estrone, bisphenol F, bisphenol B, and bisphenol A, with enrichment factors of 99.60-133.16. A molecularly imprinted polymer solid-phase microextraction fiber array (MIP-SPME fiber array) coupled with high-performance liquid chromatography-diode array detection was used for the analysis and detection of the five estrogens in milk and yogurt samples. Satisfactory recoveries were achieved ranging from 74.75-119.41% with <9.42% relative standard deviations. The developed method for the simultaneous determination of trace estrogens in food samples exhibited a limit of detection of 0.33 µg L-1. The MIP-SPME fiber array provided an available strategy for improving the selectivity and adsorption capacity of SPME for trace target component analysis in complex matrices and increasing the sensitivity of the analytical method.

Advances in Molecular Imprinting Technology for the Extraction and Detection of Quercetin in Plants.

Quercetin is a kind of flavonoid compound, which has antioxidative, anti-aging and anti-cancer effects, so it is of great importance to study the efficient extraction and highly sensitive detection of quercetin. Molecular imprinting technology has remarkable selectivity and resistance to complex matrix interference, which is often used for extracting quercetin. The methods of molecular imprinted solid phase extraction, molecularly imprinted microsphere extraction, molecularly imprinted electrochemical sensor recognition and molecularly imprinted composite material extraction of quercetin from plant samples were discussed in detail. This review provides valuable information on efficient and sensitive methods for separating and purifying quercetin in plants. It also provides a technical reference for further investigation of the separation and analysis of active ingredients in natural products.

Mucosa-associated lymphoid tissue lymphoma translocation protein 1 exaggerates multiple organ injury, inflammation, and immune cell imbalance by activating the NF-κB pathway in sepsis.

Objective: Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) modulates the inflammatory immune response and organ dysfunction, which are closely implicated in sepsis pathogenesis and progression. This study aimed to explore the role of MALT1 in sepsis-induced organ injury, immune cell dysregulation, and inflammatory storms. Methods: Septic mice were constructed by intraperitoneal injection of lipopolysaccharide, followed by overexpression or knockdown of MALT1 by tail vein injection of the corresponding lentivirus. Mouse naïve CD4+ T cells and bone marrow-derived macrophages were treated with MALT1 overexpression/knockdown lentivirus plus lipopolysaccharide. Results: In the lungs, livers, and kidneys of septic mice, MALT1 overexpression exaggerated their injuries, as shown by hematoxylin and eosin staining (all p < 0.05), elevated cell apoptosis, as reflected by the TUNEL assay and cleaved caspase-3 expression (p < 0.05 in the lungs and kidneys), and promoted macrophage infiltration, as illustrated by CD68 immunofluorescence (p < 0.05 in the lungs and kidneys). Meanwhile, in the blood, MALT1 overexpression reduced T-helper (Th)1/Th2 cells, increased Th17/regulatory T-cell ratios (both p < 0.05), promoted systematic inflammation, as revealed by tumor necrosis factor-α, interleukin-6, interleukin-1ß, and C-reactive protein (all p < 0.05), elevated oxidative stress, as shown by nitric oxide (p < 0.05), superoxide dismutase, and malondialdehyde (p < 0.05), and enhanced liver and kidney dysfunction, as revealed by an automatic animal biochemistry analyzer (all p < 0.05 except for aspartate aminotransferase). However, MALT1 knockdown exerted the opposite effect as MALT1 overexpression. Ex vivo experiments revealed that MALT1 overexpression promoted the polarization of M1 macrophages and naïve CD4+ T cells toward Th2 and Th17 cells (all p < 0.05), while MALT1 knockdown attenuated these effects (all p < 0.05). Mechanistically, MALT1 positively regulated the nuclear factor-κB (NF-κB) pathway both in vivo and ex vivo (p < 0.05). Conclusion: Mucosa-associated lymphoid tissue lymphoma translocation protein 1 amplifies multiple organ injury, inflammation, oxidative stress, and imbalance of macrophages and CD4+ T cells by activating the NF-κB pathway in sepsis.

Neoadjuvant therapy with immune checkpoint blockade, antiangiogenesis, and chemotherapy for locally advanced gastric cancer.

Despite neoadjuvant/conversion chemotherapy, the prognosis of cT4a/bN+ gastric cancer is poor. Immune checkpoint inhibitors (ICIs) and antiangiogenic agents have shown activity in late-stage gastric cancer, but their efficacy in the neoadjuvant/conversion setting is unclear. In this single-armed, phase II, exploratory trial (NCT03878472), we evaluate the efficacy of a combination of ICI (camrelizumab), antiangiogenesis (apatinib), and chemotherapy (S-1 ± oxaliplatin) for neoadjuvant/conversion treatment of cT4a/bN+ gastric cancer. The primary endpoints are pathological responses and their potential biomarkers. Secondary endpoints include safety, objective response, progression-free survival, and overall survival. Complete and major pathological response rates are 15.8% and 26.3%. Pathological responses correlate significantly with microsatellite instability status, PD-L1 expression, and tumor mutational burden. In addition, multi-omics examination reveals several putative biomarkers for pathological responses, including RREB1 and SSPO mutation, immune-related signatures, and a peripheral T cell expansion score. Multi-omics also demonstrates dynamic changes in dominant tumor subclones, immune microenvironments, and T cell receptor repertoires during neoadjuvant immunotherapy. The toxicity and post-surgery complications are limited. These data support further validation of ICI- and antiangiogenesis-based neoadjuvant/conversion therapy in large randomized trials and provide candidate biomarkers.

Osr1 Regulates Macrophage-mediated Liver Inflammation in Nonalcoholic Fatty Liver Disease Progression.

BACKGROUND & AIMS: Liver macrophage-mediated inflammation contributes to the pathogenesis of the nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Odd skipped-related 1 (Osr1) is a putative transcription factor previously reported to be involved in NASH progression; however, the underlying mechanisms remain unknown. The current study focused on the role of Osr1 in macrophage polarization and metabolism and its associated functions in the inflammation-induced pathogenesis of NASH. METHODS: OSR1/Osr1 expression patterns were compared in normal and NASH patients and mouse livers. NASH was established and compared between hepatocyte-specific Osr1 knockout (Osr1ΔHep), macrophage-specific Osr1 knockout (Osr1ΔMφ), and wild-type (Osr1F) mice fed with 3 different chronic obesogenic diets and methionine choline-deficient diet. Using genetic and therapeutic strategies in vitro and in vivo, the downstream targets of Osr1 and the associated mechanisms in inflammation-induced NASH were established. RESULTS: Osr1 was expressed in both hepatocytes and macrophages and exhibited different expression patterns in NASH. In NAFLD and NASH murine models, deleting Osr1 in myeloid cells (Osr1ΔMφ), but not hepatocytes, aggravated steatohepatitis with pronounced liver inflammation. Myeloid Osr1 deletion resulted in a polarization switch toward a pro-inflammatory phenotype associated with reduced oxidative phosphorylation activity. These inflamed Osr1ΔMφ macrophages promoted steatosis and inflammation in hepatocytes via cytokine secretion. We identified 2 downstream transcriptional targets of Osr1, c-Myc, and PPARγ and established the Osr1-PPARγ cascade in macrophage polarization and liver inflammation by genetic study and rosiglitazone treatment in vivo. We tested a promising intervention strategy targeting Osr1-PPARγ by AAV8L-delivered Osr1 expression or rosiglitazone that significantly repressed NAFLD/NASH progression in Osr1F and Osr1ΔMφ mice. CONCLUSIONS: Myeloid Osr1 mediates liver immune homeostasis and disrupting Osr1 aggravates the progression of NAFLD/NASH.

Introducing AgNPs-VB2 composites as the dual signal quenching of CeO2-AuNPs-g-CNQDs hybrids for ultrasensitive "on-off" electrochemiluminescence immunosensing of prostate specific antigen.

An ultrasensitive resonance energy transfer based "on-off" switch electrochemiluminescence (ECL) immunosensing strategy was proposed and applied for prostate specific antigen (PSA) detection. In detail, self-enhancing nanohybrids of nano-CeO2 and AuNPs decorated graphitic carbon nitride quantum dots (CeO2-AuNPs-g-CNQDs) were synthesized, which produced high ECL emission with coreactant K2S2O8 for "switch-on" state. Noticeably, due to the reversible Ce3+↔ Ce4+ reaction, nano-CeO2 could serve as highly-efficient coreaction accelerator and induce the decomposition of S2O82- into SO4• -, which endowed the g-CNQDs/K2S2O8 system with enhanced ECL emission. Moreover, AuNPs acted crucial role in promoting the electronic transmission rate and providing sites to immobilize the biomolecules. On the other hand, the AgNPs-VB2 nanocomposites were used as dual labels to quench the ECL signal of g-CNQDs-K2S2O8 system via ECL-RET, leading to the decreased ECL for "switch-off" state. On the basis of sandwich-typed immunosensing strategy, the developed ECL immunosensing platform exhibited sensitive response to PSA in a linear range of 1.0 × 10-5 _ 50 ng mL-1 with a low detection limit of 0.0045 pg mL-1 (S/N = 3). This work provided a promising tool in early clinical diagnostics of prostate cancer.

Multiparametric immune profiling of advanced cervical cancer to predict response to programmed death-1 inhibitor combination therapy: an exploratory study of the CLAP trial.

PURPOSE: Checkpoint immunotherapy is a promising treatment option for advanced cervical cancer. To aid in selecting patients for this treatment, we identified potential predictors of the response to anti-PD-1 combination therapy. METHODS: We simultaneously characterized CD8+, FoxP3+, PD-L1+, CD68+, CD31+, PANCK+, and PANCK-PD-L1+ cells at the invasive margin (IM) of tumor by multispectral imaging of tissue sections from 37 patients with advanced cervical cancer in our previous trial cohort. The densities of each cell and cell-to-cell topography were compared between the responder and non-responder groups and evaluated for their predictive value in clinical response and survival. RESULTS: CD8+ T cells, PD-L1+ cells, and PANCK-PD-L1+ immune cells showed higher densities at the IM in the responders than in the non-responders (P = 0.022, 0.0094, and 0.049, respectively). A higher density of CD8+ T cells at the IM was related to prolonged progression-free survival (PFS; P = 0.031). A higher ratio of CD68+/CD8+ cells was found in the non-responder group (P = 0.003) and related to poor PFS (P = 0.016). A higher density of PANCK-PD-L1+ immune cells within 20, 30, and 45 µm of PANCK+ tumor cells was correlated with better clinical response (P = 0.017, 0.017, and 0.02, respectively). CONCLUSIONS: Multiparametric immune profiling of CD8+ T cells, PD-L1+ cells, CD68+ macrophages and PANCK-PD-L1+ immune cells at the invasive margin may help identify patients with cervical cancer who may benefit from anti-PD-1 combination therapy. CLINICAL TRIAL REGISTRATION: ClinicalTrials. gov identifier: NCT03816553, January 25, 2019.