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Cytokines, which are important to the tumor microenvironment (TME), play critical roles in tumor development, metastasis, and immune responses. Interleukin-17(IL-17) has emerged as a key biomarker in many malignancies; however, its precise involvement in gastric cancer is less fully understood. Elevated levels of IL-17 have been observed in stomach diseases such as Helicobacter pylori infection and autoimmune gastritis, indicating that a sustained Th17 response may precede the development of gastric cancer. While IL-17 is related to inflammatory processes that may lead to cancer, its specific influence on gastric cancer development and therapy needs to be completely understood. Specifically, the release of IL-17A by diverse immune cells has been associated with both tumor development and inhibition in gastric cancer. It may impact tumor development through mechanisms such as boosting cell proliferation, inducing angiogenesis, and enabling immune cell recruitment or, conversely, suppressing tumor growth via the activation of anti-tumor immune responses. The dual role of IL-17 in cancer, along with its various effects depending on the TME and immune cell composition, highlights the complexity of its activity. Current research reveals that although IL-17 might serve as a target for immunotherapy, its therapeutic potential is hindered by its various activities. Some studies have shown that anti-IL-17 drugs may be helpful, especially when paired with immune checkpoint inhibitors, whereas others point to concerns about the validity of IL-17 in gastric cancer therapy. The lack of clinical trials and the heterogeneity of human tumors underscore the necessity for individualized treatment approaches. Further studies are needed to identify the specific mechanisms of IL-17 in gastric cancer and to design targeted therapeutics appropriately.

Quantum cascade lasers (QCLs) in the mid-infrared (MIR) hold significant potential for widespread applications in both military and civilian contexts. However, the utility of present single-chip QCLs is hampered by issues such as low output power and subpar beam quality. This study addresses these limitations by employing spectral beam combining (SBC) based on a diffraction grating, with an aim to enhance both power and beam quality of MIR QCLs. Coaxial power synthesis of three single-chip QCLs (around 4.75 μm) is achieved experimentally, importantly, the beam quality did not decrease after combining, essentially maintaining the same quality as before combining. It is proposed that there are four main factors affecting the combining efficiency, namely operating optical power (or driving current) of the chips, individual differences in QCL chips, diffraction grating, and reflectivity of feedback mirror, and their effects on the combining efficiency are discussed separately. This study confirms that SBC is an effective way to obtain high-power and high-beam quality MIR QCL sources, and lays a research foundation for more beam spectral combining.

BackgroundMetabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease. Body mass index (BMI) is the most used obesity index but has important limitations. The weight-adjusted waist index (WWI) is a novel obesity metric and accurately reflects body composition. We explored the association of WWI with all-cause and cardiovascular disease (CVD) mortality in MASLD.MethodsAdult participants with MASLD were included from NHANES 1999-2018. WWI was calculated by dividing the waist circumference (WC) by the square root of body weight. MASLD was diagnosed by the presence of hepatic steatosis and at least one cardiometabolic risk factor in the absence of other causes of steatosis. A fatty liver index ≥60 suggested the presence of hepatic steatosis. Mortality data was obtained by prospectively linking to the National Death Index. Multivariate Cox proportional hazards regression analyses were used to explore these associations and multiple adjustment models were constructed including crude, partial, and fully adjusted models.ResultsAfter adjusting for all covariates including BMI, WWI remained positively and linearly associated with all-cause and CVD mortality in MASLD (hazard ratios [HR] 1.247 and 1.218, respectively). Higher WWI was associated with a significantly increased risk of mortality (both p for trend

The incidence of colorectal cancer is relatively high in our country, with the majority of patients being diagnosed at an advanced stage. For individuals with advanced-stage colorectal cancer, conversion or neoadjuvant therapy is frequently necessitated to facilitate surgical intervention and achieve a curative effect. And about 10% to 30% of colon cancer patients are complicated with intestinal obstruction. Surgical intervention remains the primary treatment for managing intestinal obstructions, albeit with a considerable risk of perioperative mortality and an increased likelihood of postoperative complications. PDT, as a neoadjuvant treatment for colon cancer, can shrink the local tumor and relieve obstruction, and is effective in colon cancer combined with obstruction. Robotic surgery has the advantages of high stability and low trauma, and compared with laparoscopic colon cancer surgery, robotic surgery can achieve better results. Fluorescent laparoscopic clarifies the location and size of the tumor lesion, allowing for greater precision when removing colon cancer lesions in robotic surgery. Therefore, in the treatment of colon cancer, PDT can offer an opportunity for surgery after relieving obstruction in patients with obstructive colon cancer. Additionally, when combined with fluorescent laparoscopic robotic colon cancer surgery, it provides a novel treatment approach for patients with obstructive colon cancer. Preoperative photodynamic neoadjuvant therapy combined with robotic colon cancer surgery has not yet been reported. Here, we report a case of colon cancer with obstruction, preoperative TNM stage was T4N1, and the lesion had caused intestinal stenosis. After four sessions of PDT, the patient’s intestinal lumen was unobstructed and the lesion had regressed. After evaluation, fluorescent laparoscopic localization and visualization of lymph nodes combined with robotic colon cancer resection were performed. Postoperative pathology showed that the patient’s tumor regression grade was grade 1. The patient’s tumor was completely resected with good resection effect. No tumor invasion was found on both sides of the resection margin, and the patient did not relapse after surgery.

Sequential working memory (SWM), referring to the temporary storage and manipulation of information in order, plays a fundamental role in brain cognitive functions. The serial position effect refers to the phenomena that recall accuracy of an item is associated to the order of the item being presented. The neural mechanism underpinning the serial position effect remains unclear. The synaptic mechanism of working memory proposes that information is stored as hidden states in the form of facilitated neuronal synapse connections. Here, we build a continuous attractor neural network with synaptic short-term plasticity (STP) to explore the neural mechanism of the serial position effect. Using a delay recall task, our model reproduces the the experimental finding that as the maintenance period extends, the serial position effect transitions from the primacy to the recency effect. Using both numerical simulation and theoretical analysis, we show that the transition moment is determined by the parameters of STP and the interval between presented stimulus items. Our results highlight the pivotal role of STP in processing the order information in SWM.

Thermal action is a crucial process in laser processing. The classical Fourier heat conduction theory, which assumes an infinite speed of heat propagation, is commonly applied to describe steady-state and mild transient thermal processes. However, under the influence of ultra-short pulse lasers, such as those with picosecond and femtosecond durations, the heat propagation speed within the material is finite and deviates from Fourier’s law. This article addresses the unique characteristics of heat conduction in materials subjected to ultra-short pulse laser exposure by integrating Fourier’s law with the Gaussian distribution of the actual pulse laser output power density and the material’s optical absorption properties. It introduces a time variable to establish a time-dependent heat conduction equation. This equation is numerically analyzed using a difference algorithm. Based on this, simulation and experimental studies on the processing of dental hard tissues with a 1064 nm ps laser were conducted. The results show that the experimental processing depths were slightly larger than the simulation results, which may be due to damage to the dental hard tissues and the thermomechanical effects during processing. The results offer a technical reference for adjusting laser parameters in the ultra-short pulse laser processing technique.

Invasion or aggregation of marine organisms in cooling water intake systems (CWIS) has gradually become an important problem affecting the safety of nuclear power plants with environmental and climate changes. In this study, a 3-dimensional numerical model (TELEMAC-3D) was used to determine the impingement probability in a typical nuclear power plant with a once-through cooling system, and the effect on CWIS safety. The factors controlling impingement probability were also analyzed. Results show that (1) impingement probability decreased rapidly with an increase in distance from the CWIS. In addition, the distance of the impingement effect of a nuclear power plant with six units was mainly within 1 km of the CWIS. (2) Impingement probability increased with water withdrawal, and as distance to the CWIS increased, the increase in probability increased. (3) Generally, an increase in tide strength led to a decrease impingement probability. (4) Near the CWIS, the impingement probabilities of areas upstream or downstream of the CWIS along the tidal flow direction were much higher than those not in those areas. (5) An increase in water depth significantly reduced impingement probability. When the water depth of the CWIS increased from 5 m to 15 m, impingement probability was reduced up to 30%. Based on the above findings, the following suggestions were made to minimize the impingement effects on CWIS safety: first, the CWIS of coastal nuclear power plants should be set in an area with low aquatic biomass, strong tides, deep water, and few surface species within the range of 1 km, and second, the amount of cooling water withdrawal or velocity should be reduced as much as possible.

At present, nano-carrier materials with antibacterial activity are of great significance. Due to the widespread resistance of many pathogenic microorganisms, it has seriously threatened human health. The natural antimicrobial substances extracted from fruits and vegetables can significantly improve their stability combined with nano-carrier materials. The resistance of pathogenic microorganisms will be substantially reduced, greatly enhancing the effect of active antimicrobial substances. Nanotechnology has excellent research prospects in the food industry, antibacterial preservation, food additives, food packaging, and other fields. This paper introduces nano-carrier materials and preparation techniques for loading and encapsulating active antibacterial substances in detail by constructing a nano-release system for active antibacterial substances. The antibacterial effect can be achieved by protecting them from adverse external conditions and destroying the membrane of pathogenic microorganisms. The mechanism of the slow release of the bacteriostatic active substance is also described. The mechanism of carrier loading and release is mainly through non-covalent forces between the bacteriostatic active substance and the carrier material, such as hydrogen bonding, π-π stacking, van der Waals forces, electrostatic interactions, etc., as well as the loading and adsorption of the bacteriostatic active substance by the chemical assembly. Finally, its wide application in food and medicine is introduced. It is hoped to provide a theoretical basis and technical support for the efficient utilization and product development of bacteriostatic active substances.

A symmetric grating is proposed to obtain higher output power in spectral beam combination by increasing the number of lasers and spectral utilization. The grating allows laser beams to be incident from both sides of the grating normal to achieve coaxial beam combining, so the number of beams and the combined output power are doubled compared with the traditional grating under the same spectral line-width. The grating is designed with the central wavelength of 4.65 μm, and the calculation results show that this grating is very advantageous for spectral beam combining, especially for the light waves in the range 4.55–4.71 μm, where their diffraction efficiencies are high (over 80%) and correspond to a wide and linear range of incidence angles. Meanwhile, based on the symmetric gratings we further propose a circular grating to achieve the same frequency spectral beam combining. This beam combining design will not increase the laser spectral line width while enhancing the laser power, reducing the requirements for the unit laser spectral line width, which is very meaningful in some application fields and will further enrich the research of spectral beam combining.

PurposeThis study aims to investigate the prognostic value of composition and spatial architecture of tumor-infiltrating lymphocytes (TILs) as well as PDL1 expression on TILs subpopulations in nasopharyngeal carcinoma (NPC).MethodsA total of 121 patients with NPC were included and divided into two groups: favorable (n = 68) and unfavorable (n = 53). The archived tumor tissues of the included patients were retrieved, and a tissue microarray was constructed. The density and spatial distribution of TILs infiltration were analyzed using the multiplex fluorescent immunohistochemistry staining for CD3, CD4, CD8, Foxp3, cytokeratin (CK), PDL1, and 4′,6-diamidino-2-phenylindole (DAPI). The infiltration density of TILs subpopulations and PDL1 expression were compared between the two groups. The Gcross function was calculated to quantify the relative proximity of any two types of cells. The Cox proportional hazards regression model was used to identify factors associated with overall survival (OS) and disease-free survival (DFS).ResultsThe densities of regulatory T-cells (Tregs), effector T-cells (Teffs), PDL1+ Tregs, and PDL1+ Teffs were significantly higher in patients with unfavorable outcomes. PDL1 expression on tumor cells (TCs) or overall TILs was not associated with survival. Multivariate analysis revealed that higher PDL1+ Tregs infiltration density was independently associated with inferior OS and DFS, whereas Tregs infiltration density was only a prognostic marker for DFS. Spatial analysis revealed that unfavorable group had significantly stronger Tregs and PDL1+ Tregs engagement in the proximity of TCs and cytotoxic T lymphocyte (CTLs). Gcross analysis further revealed that Tregs and PDL1+ Tregs were more likely to colocalize with CTLs. Moreover, increased GTC : Treg (Tregs engagement surrounding TCs) and GCTL : PDL1+ Treg were identified as independent factors correlated with poor outcomes.ConclusionTILs have a diverse infiltrating pattern and spatial distribution in NPC. Increased infiltration of Tregs, particularly PDL1+ Tregs, as well as their proximity to TCs and CTLs, correlates with unfavorable outcomes, implying the significance of intercellular immune regulation in mediating disease progression.

ObjectivesThis study aimed to investigate the clinical and biochemical profiles of patients with imported malaria infection between 1 January 2011 and 30 April 2022 and admitted to the Fourth People’s Hospital of Nanning.MethodsThis cohort study enrolled 170 patients with conformed imported malaria infection. The clinical and biochemical profiles of these participants were analyzed with malaria parasite clearance, and signs and symptoms related to malaria disappearance were defined as the primary outcome. A multivariable logistic regression model was used to evaluate the odds ratios (ORs) with 95% confidence intervals (CIs) for cerebral malaria. The Cox model was used to estimate the hazard ratios (HRs) with 95% CIs for parasite clearance.ResultsAdenosine deaminase and parasitemia were found to be independent risk factors for severe malaria in patients with imported malaria (OR = 1.0088, 95% CI: 1.0010–1.0167, p = 0.0272 and OR = 2.0700, 95% CI: 1.2584–3.4050, p = 0.0042, respectively). A 0.5–standard deviation (SD) increase of variation for urea (HR = 0.6714, 95% CI: 0.4911–0.9180), a 0.5-SD increase of variation for creatinine (HR = 0.4566, 95% CI: 0.2762–0.7548), a 0.25-SD increase of variation for albumin (HR = 0.4947, 95% CI: 0.3197–0.7653), a 0.25-SD increase of variation for hydroxybutyrate dehydrogenase (HR = 0.6129, 95% CI: 0.3995–0.9402), and a 1.0-SD increase of variation for ferritin (HR = 0.5887, 95% CI: 0.3799–0.9125) were associated with a higher risk for increased parasite clearance duration than a low-level change.ConclusionsAspartate aminotransferase, urea, creatinine, albumin, hydroxybutyrate dehydrogenase, and ferritin are useful biochemical indicators in routine clinical practice to evaluate prognosis for imported malaria.

Objective: Polyethylene glycol recombinant human growth hormone (PEG-rhGH, Jintrolong®) is the first long-acting rhGH preparation that is approved to treat children with growth hormone deficiency (GHD) in China. Clinical experience with dose selections of PEG-rhGH is scarce. The present study compared the efficacy and safety of a lower dose to increase dosing regimens of PEG-rhGH treatment.Methods: A multicenter, randomized, open-label, dose-comparison clinical study was conducted to compare the improvements in the height standard deviation score (Ht SDS), height velocity (HV), insulin-like growth factor-1 (IGF-1) SDS, and safety profiles of children with GHD who are treated with 0.2 mg/kg/week of PEG-rhGH dose or 0.14 mg/kg/week for 26 weeks.Results: Ht SDS, HV, and IGF-1 SDS increased significantly after PEG-rhGH treatment in the two dose groups (p < 0.05). The improvements of Ht SDS, HV, and IGF-1 SDS were more significant in the high-dose group than in the low-dose group (p < 0.05). Ht SDS improvement in low-dose group was not non-inferiority to that in the high-dose group (p = 0.2987). The incidences of adverse events were comparable between the two groups.Conclusion: The improvements of Ht SDS, HV, and IGF-1 SDS were more significant in the high-dose group than in the low-dose group (p < 0.05). PEG-rhGH at the dose of 0.14 mg/kg/week was effective and safe for children with GHD.Clinical Trial Registration:clinicaltrials.gov, identifier NCT02908958.

Cruciferous vegetables are rich in glucosinolates, which can be metabolized to produce the antitumor compound indole-3-carbinol (I3C). The conventional solvent extraction method for I3C is inefficient. To improve the extraction efficiency of I3C from cruciferous vegetables, we prepared a metal-organic framework (MOF) material (Fe3O4@Zn-Al-LDH@B-D-MIL-100). First, Fe3O4 nanoparticles were introduced to layered double hydroxides by in situ polymerization. Then, the MOF material was grown on the surface of the layered double hydroxide by co-precipitation and the layer-by-layer self-assembly method. This gave Fe3O4@Zn-Al-LDH@B-D-MIL-100, which was characterized using a variety of techniques. The results showed that Fe3O4@Zn-Al-LDH@B-D-MIL-100 had a double-layer porous structure, excellent superparamagnetism (11.54955 emu/g), a large specific surface area (174.04 m2/g), and a pore volume (0.26 cm3/g). The extraction conditions for I3C were optimized. Non-linear fitting of the static adsorption model showed that the adsorption was mainly monolayer. Fe3O4@Zn-Al-LDH@B-D-MIL-100 had fast adsorption kinetics and could extract 95% of I3C in 45 min. It is superior to the traditional solvent extraction method because of its high enrichment efficiency in a short time and environmental friendliness. The successful preparation of the new nanomaterial will provide a new reference for the enrichment and extraction of the I3C industry.

ObjectivesTo analyze the incidence and spread of lymph node metastasis (LNM) and the effectiveness of prophylactic neck irradiation in patients with SNSCC.MethodsA total of 255 patients with SNSCC were retrospectively reviewed. The LNM spread pattern was revealed. The clinical parameters related to LNM, and the prognostic value of elective neck irradiation (ENI) were assessed. A 1:1 matching with propensity scores was performed between ENI group and observation (OBS) group.ResultsThe initial LNM rate was 20.8%, and the regional recurrence (RR) rate was 7.5%. Lymphatic spreading in SNSCC followed the common trajectories: a. level Ib ➔ level II ➔ level Va/level III/IV lymph nodes (LNs); b. retropharyngeal lymph nodes (RPLNs) ➔ level II LNs. The most frequently involved site was level II LNs (16.1%), followed by level Ib LNs (10.2%), RPLNs (4.7%), level III LNs (3.2%), level Va LNs (1.6%), level IVa LNs (1.4%) and level VIII LNs (0.8%). The median follow-up time was 105 months. The 5-year overall survival (OS) was 55.7% for N0 patients and 38.5% for patients with initial N+ or N- relapse (p = 0.009). After PSM, the 5-year regional recurrence-free survival was 71.6% and 94.7% (p = 0.046) in OBS and ENI group, respectively. The multivariate analysis showed that ENI (p = 0.013) and absence of nasopharynx involvement (p = 0.026) were associated with a significantly lower RR rate.ConclusionsPatients with LNM had poorer survival than those who never experienced LNM. Lymphatic spread in SNSCC followed predictable patterns. ENI effectively reduced the RR rate in patients at high risk.

Selenium-enriched mung bean (Se-MB) is a combination of mung bean (MB) and selenium (Se), which have a variety of potential biological activities. However, little is known about the skincare activity of Se-MB. The chemical composition of Se-MB fermentation broth (Se-MBFB) was analyzed to investigate the whitening, moisturizing, and anti-aging activities of Se-MBFB. The tyrosinase inhibition, anti-melanogenic in melanocytes (B16F10 cells), and moisturizing effect in human dermal fibroblasts (HDFs) were analyzed. Besides, the free radical scavenging activity of Se-MBFB was assessed in vitro. To verify the in vivo effects and the potential of practical applications of Se-MBFB, a clinical trial was conducted on the participants: 31 Chinese women aged 25–60 years, with no pigmentation disorder, no illness, no history of hypersensitivity reaction, and no use of skincare product on the face. The participants used an Se-MBFB masque for 15-20 min after cleaning the face. The measurement points were Week 0, 2, and 4 (W0, W2, and W4) after using the masque, and target sites were cheek and canthus. The following parameters were recorded on the target sites at each visit: melanin index, skin color, cuticle moisture content, transepidermal water loss, and crow's feet. The results demonstrated that Se-MBFB was rich in polyphenols, peptides, and γ-aminobutyric acid (GABA), displayed significant free radical scavenging and tyrosinase inhibiting activities, decreased the synthesis of melanin, and upregulated the aquaporin-3 (AQP3) expression. The test of the Se-MBFB mask showed that after 4 weeks of using the Se-MBFB facemask, the faces of the participants became whiter with reduced wrinkles and increased moisture content. Se-MB possessed the excellent whitening, moisturizing, and antioxidant efficacy, which could lay a scientific foundation for utilization and development of skincare products of Se-MB and its related industrial cosmetics products.

Carbendazim (CBZ), a systemic, broad-spectrum benzimidazole fungicide, is widely used to control fungal diseases in agricultural products. Its residues might pose risks to human health and the environment. Therefore, it is warranted to establish a rapid and reliable method for its residual quantification. Herein, we proposed a competitive assay that combined aptamer (DNA) specific recognition and bimetallic nanozyme gold@platinum (Au@Pt) catalysis to trace the CBZ residue. The DNA was labeled onto bimetallic nanozyme Au@Pt surface to produce Au@Pt probes (Au@Pt-DNA). The magnetic Fe3O4 was functionalized with a complementary strand of DNA (C-DNA) to form Fe3O4 probes (Fe3O4-C-DNA). Subsequently, the CBZ and the Fe3O4 probes competitively react with Au@Pt probes to form two Au@Pt-DNA biosensors (Au@Pt-ssDNA-CBZ and Au@Pt-dsDNA-Fe3O4). The Au@Pt-ssDNA-CBZ biosensor was designed for qualitative analysis through a naked-eye visualization strategy in the presence of CBZ. Meanwhile, Au@Pt-dsDNA-Fe3O4 biosensor was developed to quantitatively analyze CBZ using a multifunctional microplate reader. A competitive assay based on the dual-mode Au@Pt-DNA biosensors was established for onsite sensitive determination of CBZ. The limit of detection (LOD) and recoveries of the developed assay were 0.038 ng/mg and 71.88-110.11%, with relative standard deviations (RSDs) ranging between 3.15 and 10.91%. The assay demonstrated a good correlation with data acquired from liquid chromatography coupled with mass spectrometry/mass spectrometry analysis. In summary, the proposed competitive assay based on dual-mode Au@Pt-DNA biosensors might have a great potential for onsite sensitive detection of pesticides in agro-products.

The demand for Chinese chives is growing as they are also rich in vitamins, fiber, and sulfur nutrients. Chinese chives should be sprayed with imidacloprid to control pests and diseases to safeguard their yield and to meet the demands of East Asian consumers for Chinese chives. Overspraying of imidacloprid can lead to residues in Chinese chives, posing a severe risk to human health. To reduce the harmful effects of imidacloprid residues on humans, we investigated the imidacloprid dissipation pattern and the final residue on Chinese chives using the quick, easy, cheap, effective, rugged, and safe (QuEChERS) method combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Good linearity (R2= 0.9988), accuracy (expressed as recovery % of 78.34–91.17%), precision [expressed as relative SDs (RSDs) of 0.48–6.43%], and sensitivity [a limit of quantification (LOQ) ≤ 8.07 × 104 mg/kg] were achieved. The dissipation dynamics were consistent with the first-order kinetics, with a half-life of 2.92 days. The final residual levels on Chinese chives were 0.00923–0.166 mg/kg, which is lower than the maximum residue limits (MRLs) of 1 mg/kg for imidacloprid on Chinese chives. A risk assessment index of

Turbulent mixing above rough topography is crucial for the vertical motions of deep water and the closure of the meridional overturning circulation. Related to prominent topographic features, turbulent mixing not only exhibits a bottom-intensified vertical structure but also displays substantial lateral variation. How turbulent mixing varies in the upslope direction and its impact on the upwelling of deep water over sloping topography remains poorly understood. In this study, the notable multihump structure of the bottom-intensified turbulent diffusivity in the upslope direction of a seamount in the South China Sea (SCS) is revealed by full-depth fine-resolution microstructure and hydrographic profiles. Numerical experiments indicate that multihump bottom-intensified turbulent mixing around a seamount could lead to multiple cells of locally strengthened circulations consisting of upwelling (downwelling) motions in (above) the bottom boundary layer (BBL) that are induced by bottom convergence (divergence) of the turbulent buoyancy flux. Accompanied by cyclonic (anticyclonic) flow, a three-dimensional spiral circulation manifests around the seamount topography. These findings regarding the turbulent mixing and three-dimensional circulation around a deep seamount provide support for the further interpretation of the abyssal meridional overturning circulation.

PurposeThe high intracranial efficacy of targeted therapeutic agents poses a challenge in determining the optimal sequence of local radiation therapy (RT) and systemic treatment with tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) patients with brain metastasis (BM). Therefore, we conducted a cohort study to elucidate the appropriate treatment strategy, either upfront RT or deferred RT including a toxicity assessment, in these patients.Patients and MethodsWe retrospectively evaluated patients with gene-driven BMs from a single institution and divided them into deferred and upfront RT groups. Survival was estimated using a log-rank test. Intracranial progression was estimated using Fine-Gray competing risks model. Cox proportional hazards regression was performed for multivariable analysis in the entire group and subgroups.ResultsAmong the 198 eligible patients, 94 and 104 patients received deferred and upfront RT, respectively. The upfront RT group showed a lower intracranial progression risk with an adjusted sub-distribution hazard ratios of 0.41 (95% CI, 0.30–0.57) than did the deferred RT group (median intracranial progression-free survival [iPFS], 19.9 months vs. 11.1 months; p < 0.001). The median overall survival (OS; 43.2 months vs. 49.1 months, p = 0.377) and BM-specific survival (92.1 months vs. 82.9 months, p = 0.810) after salvage therapy were not significantly different between the upfront and deferred groups. Among patients with progressed extracranial disease, the deferred RT group showed significantly better OS than did the upfront RT group (44.0 vs. 28.1 months, p = 0.022). Grade 3–4 treatment-related adverse events were rare, and similar toxicities were observed between the two groups.ConclusionCompared to the deferred RT group, the upfront RT group achieved longer iPFS and similar survival outcomes in most patients with gene-driven NSCLC BM, although patients with progression of extracranial disease might benefit from deferred RT. Both groups showed well-tolerated toxicities.Trial registration IDNCT04832672.

To test the pharmacokinetics and toxicology of whole organs and tissues after intradiscal injection of simvastatin in rabbits. To provide the information needed to support human clinical trials. Twelve male and twelve female rabbits were randomly divided into four groups: control group (0 mg/ml), low dose group (0.1 mg/ml), medium dose group (1 mg/ml) and high dose group (10 mg/ml). Simvastatin at different concentrations of 10 μl was injected into L3/4, L4/5 and L5/6 intervertebral discs in each group. Poly (ethylene glycol) -poly (lactic-co-glycolic acid) -poly (ethylene glycol) (PEG-PLGA-PEG) polymer as the drug carrier. The pharmacokinetics of blood samples were measured by LC-MS/MS. Cerebrospinal fluid was obtained and the drug concentration was measured. Blood routine, blood biochemistry and urine of all animals were analyzed and evaluated. The heart, kidney, liver and spleen of each animal were observed and weighed. The intervertebral disc tissues were stained with hematoxylin and hematoxylin (H&E), and then qualitatively analyzed by optical microscopy. 28 days after intradiscal injection of simvastatin, 28 days after simvastatin intradiscal injection, there was no significant difference between the weight, food residue, blood routine, blood biochemistry, urine routine results and the weight of each organ in the four groups (p > 0.05). The serum concentration of simvastatin is lower than the lowest measurable concentration. The histological score of the intervertebral disc in the high-dose group was significantly higher than that in the other three groups at 28 days (p < 0.05). Three doses of simvastatin were injected into male and female animals respectively, showing no toxic effects. Microscopic histological evaluation of the intervertebral disc showed that the high dose group (10 mg/ml) had damage to the intervertebral disc tissue.

To study the effect of intradiscal injection of simvastatin on discogenic pain in rats and its possible mechanism, 30 adult female rats were used in this experiment. Twenty rats were randomly divided into sham operation group (Control group), intervertebral disk degeneration group (DDD group), intervertebral disk degeneration + hydrogel group (DDD + GEL group), and intervertebral disk degeneration + simvastatin group (DDD + SIM group). The mechanical pain threshold and cold sensation in rats were measured. The contents of NF-kappa B1, RelA, GAP43, SP, CGRP, TRPM 8, IL-1β, and TNF-α in the intervertebral disk (IVD), the corresponding contents of dorsal root ganglion (DRG) and plantar skin GAP43 and TRPM 8 were quantitatively detected by PCR. The corresponding IVDs were stained to detect their degeneration. There was no significant difference in the mechanical pain threshold between the groups at each time point. From the first day to the 8th week after surgery, the cold-sensing response of the DDD group was significantly higher than that of the Control group (P < 0.05). At 7 and 8 weeks postoperatively, the cold-sensing response of the DDD + SIM group was significantly lower than that of the DDD + GEL group (P < 0.05). The levels of NF-κB1, RelA, GAP43, SP, CGRP, TRPM8, IL-1β, and TNF-α in the IVD of DDD + SIM group were significantly lower than those in DDD group (P < 0.05). The content of GAP43 and TRPM8 in rat plantar skin decreased significantly and TRPM8 in DRG decreased significantly (P < 0.05).

Drug residues, organic dyes, heavy metals, and other chemical pollutants not only cause environmental pollution, but also have a serious impact on food safety. Timely and systematic summary of the latest scientific advances is of great importance for the development of new detection technologies. In particular, molecularly imprinted polymers (MIPs) can mimic antibodies, enzymes and other biological molecules to recognize, enrich, and separate contaminants, with specific recognition, selective adsorption, high affinity, and strong resistance characteristics. Therefore, MIPs have been widely used in chemical analysis, sensing, and material adsorption. In this review, we first describe the basic principles and production processes of molecularly imprinted polymers. Secondly, an overview of recent applications of molecularly imprinted polymers in sample pre-treatment, sensors, chromatographic separation, and mimetic enzymes is highlighted. Finally, a brief assessment of current technical issues and future trends in molecularly imprinted polymers is also presented.

Gastric cancer (GC) is a complex and heterogeneous disease, making it difficult to ascertain the optimal therapeutic approach for individual GC patients. Stromal and immune cell infiltration in GC has a strong correlation with clinical outcomes; however, the underlying mechanisms that drive immunosuppression remain vastly undiscovered. Recent studies validated that anthrax toxin receptor 1 (ANTXR1) is aberrantly expressed in several cancers and holds promise as a new therapeutic target for cancer. However, its immunological roles in GC are still unclear. Here, we show that we identify the distinct stromal and immune cell infiltration in GC between the high and low ANTXR1 expression group by analyzing genomic data. Clinically, ANTXR1 is highly expressed in GC and correlates with adverse clinicopathological characteristics. Additionally, high ANTXR1 expression is linked to markedly poor clinical outcomes and resistance to chemotherapy, whereas the low ANTXR1 expression group is correlated with better outcomes and response to chemotherapy in GC patients. We further revealed the differential landscape of somatic tumor mutation burden (TMB) between the two groups and observed that patients with high ANTXR1 expression suffered from a lower TMB, potentially leading to less sensitivity to checkpoint therapy. Molecularly, results displayed that ANTXR1 is an immunosuppressive element, which may perform its function via promoting the secretion of immunosuppressive factors that play a significant role in modulating tumor-associated fibroblast transformation, M2 macrophage polarization, and T cell exhaustion. Gene set enrichment analysis revealed that cancer-related pathways including epithelial-to-mesenchymal transition, focal adhesion, and transforming growth factor-β (TGF-β) signaling pathways were enriched in high ANTXR1 expression tumors. Our work suggests that ANTXR1 could not only serve as a valuable prognostic biomarker in GC but also be deemed as a potential immunotherapeutic target and useful biomarker of sensitivity to chemotherapy.

ObjectiveTo investigate the prevalence and distribution of cervical lymph node metastasis (LNM) in locally advanced supraglottic squamous cell carcinoma (LASCC) and guide the delineation of clinical lymph node target volumes.Materials and MethodsWe reviewed patients defined as LASCC from January 2000 to December 2017 in our hospital. The primary tumor was operated on using partial or total laryngectomy, and all patients underwent bilateral neck dissection (levels II–IV at least). Univariate and multivariate logistic regressions were used to find risk factors associated with LNM.ResultsA total of 206 patients were enrolled. In the whole group, the rate of ipsilateral metastasis (IM) was 60.9% (67 patients), whereas contralateral metastasis was 25.5% (28 patients). Only positive ipsilateral lymph nodes contributed to contralateral metastasis (p = 0.001). Seventy-six cases were diagnosed with clinical positive lymph nodes (cN+). IM of primary lesions mainly located within the unilateral sites (n = 49 patients) was detected in levels II, III, and IV with lymph node metastasis ratios of 73.5% (36 patients), 63.3% (31 patients), and 20.4% (10 patients), respectively, and contralateral metastasis of 36.7% (18 patients), 16.3% (8 patients), and 6.1% (3 patients), respectively. Involvement of level II or III was associated with metastasis of level IV. No one developed contralateral level IV involvement without metastasis of contralateral levels II and III. A total of 130 cases had clinically negative neck lymph nodes (cN0). The prevalence of occult metastasis (OM) was 35.4%. Among 62 patients with unilateral lesions, the rates of OM to ipsilateral neck levels II, III, and IV were 21, 11.1, and 1.6%, respectively, whereas contralateral neck levels were 6.3, 4.8, and 0%, respectively. In terms of the risk factors, histopathological differentiation was related to OM (p = 0.003). Two of 25 people were with level VIb metastasis, and both of them were with subglottic involvement.ConclusionNeck levels II to IV are most frequently involved and should be included in clinical target volume (CTV) in cN+ patients. Contralateral IV may be omitted when contralateral levels II and III are negative. In cN0 patients, ipsilateral levels II and III are suggested to be included in the CTV, whereas whether contralateral levels II and III should be included needs further research.

Purpose: To explore the efficacy of concomitant chemotherapy in intensity-modulated radiotherapy (IMRT) to treat stage II nasopharyngeal carcinoma (NPC).Methods and Materials: In this randomized phase 2 study [registered with ClinicalTrials.gov (NCT01187238)], eligible patients with stage II (2010 UICC/AJCC) NPC were randomly assigned to either IMRT alone (RT group) or IMRT combined with concurrent cisplatin (40 mg/m2, weekly) (CCRT group). The primary endpoint was overall survival (OS). The second endpoints included local failure-free survival (LFFS), regional failure-free survival (RFFS), disease-free survival (DFS), distant metastasis-free survival (DMFS), and acute toxicities.Results: Between May 2010 to July 2012, 84 patients who met the criteria were randomized to the RT group (n = 43) or the CCRT group (n = 41). The median follow-up time was 75 months. The OS, LFFS, RFFS, DFS, and DMFS for the RT group and CCRT group were 100% vs. 94.0% (p = 0.25), 93.0% vs. 89.3% (p = 0.79), 97.7% vs. 95.1% (p = 0.54), 90.4% vs. 86.6% (p = 0.72), and 95.2% vs. 94.5% (p = 0.77), respectively. A total of 14 patients experienced disease failure, 7 patients in each group. The incidence of grade 2 to 4 leukopenia was higher in the CCRT group (p = 0.022). No significant differences in liver, renal, skin, or mucosal toxicity was observed between the two groups.Conclusion: For patients with stage II NPC, concomitant chemotherapy with IMRT did not improve survival or disease control but had a detrimental effect on bone marrow function.

Impaired wound healing is one of the major complications of diabetes, involving prolonged inflammation, delayed re-epithelialization, and consistent oxidative stress. The detailed mechanism remains unclear, and there is currently no effective treatment for diabetic wound healing. In this study, we aim to investigate the potential role and effect of nuclear factor erythroid-2–related factor-2 (Nrf2) activation on diabetic wound healing. In vitro experiments in rat macrophages showed that hyperglycemia treatment suppresses Nrf2 activation, resulting in oxidative stress with decreased expression of antioxidant genes, including NAD(P)H:quinone oxidoreductase 1 and heme oxygenase 1, together with increased secretion of proinflammatory cytokines, including interleukin 1β (IL1β), IL6, and monocyte chemoattractant protein-1. Both Nrf2 overexpression and Nrf2 activator dimethyl fumarate (DMF) treatment significantly ameliorated oxidative stress and inflammation. On the other hand, both Nrf2 knockdown or Nrf2 inhibitor ML385 mimicked the effect of diabetes. Further in vivo experiments in rats showed that DMF treatment significantly accelerated wound healing in streptozocin-induced diabetic rats with increased expression of antioxidant enzymes and decreased secretion of proinflammatory cytokines, while Nrf2 inhibitor ML385 mimicked the effect of diabetes. We conclude that Nrf2 activation accelerates impaired wound healing by ameliorating diabetes-mediated oxidative stress and inflammation. This provides a new clinical treatment strategy for diabetic wound healing using Nrf2 activator DMF.

Delayed wound healing in diabetic patients is a serious diabetic complication, resulting in major health problems as well as high mortality and disability. The detailed mechanism still needs to be fully understood. In this study, we aim to investigate potential mechanisms and explore an efficient strategy for clinical treatment of diabetic wound healing. Human umbilical endothelial cells were exposed to hyperglycemia for 4 days, then switched to normoglycemia for an additional 4 days. The cells were harvested for the analysis of reactive oxygen species (ROS) generation, gene expression and VEGF signaling pathway. Furthermore, the diabetic wound model was established in rats for the evaluation of wound healing rates under the treatment of either ERβ agonist/antagonist or SOD mimetic MnTBAP. Our results show that transient hyperglycemia exposure results in persistent ROS overgeneration after the switch to normoglycemia, along with suppressed expression of ERβ, SOD2, and the VEGF signaling pathway. Either ERβ expression or activation diminishes ROS generation. In vivo experiments with diabetic rats show that ERβ activation or SOD mimetic MnTBAP diminishes ROS generation in tissues and accelerates diabetic wound healing. Transient hyperglycemia exposure induces ROS generation and suppresses ERβ expression, subsequently resulting in SOD2 suppression with additional elevated ROS generation. This forms a positive-feed forward loop for ROS generation with persistent oxidative stress. ERβ expression or activation breaks this loop and ameliorates this effect, thereby accelerating diabetic wound healing. We conclude that ERβ accelerates diabetic wound healing by ameliorating hyperglycemia-induced persistent oxidative stress. This provides a new strategy for clinical treatment of diabetic wound healing based on ERβ activation.

Background: Breast cancer is a very common cancer with significant premature mortality in women. In this study, we show that HKDC1 expression in breast cancer cells is increased significantly. We aim to investigate the detailed mechanism for the regulation of HKDC1 expression and its potential contribution to tumorigenesis.Methods: Gene expression was evaluated by real time PCR, western blotting, and immunohistochemistry. The mechanism for PGC1β/SREBP1-mediated HKDC1 expression was investigated using luciferase reporter assay, chromatin immunoprecipitation, and siRNA techniques. In addition, HKDC1 was overexpressed or knocked down by lentivirus to evaluate the potential effect on in vitro cell proliferation, glucose uptake, mitochondrial function, apoptosis, and reactive oxygen species (ROS) formation. Furthermore, an in vivo xenograft tumor development study was employed to investigate the effect of HKDC1 on tumor growth and mouse survival.Results: HKDC1 is highly expressed in both breast cancer cells and clinical tumor tissues. HKDC1 expression is upregulated and co-activated by PGC1β through SREBP1 binding motif on the HKDC1 promoter. HKDC1 is located on the mitochondrial membrane and regulates the permeability transition pore opening by binding with VDAC1, subsequently modulating glucose uptake and cell proliferation. Overexpression of HKDC1 increases while knockdown of HKDC1 decreases in vitro breast cancer cell proliferation and in vivo tumor growth, metastasis, and mouse survival.Conclusions: PGC1β regulates breast cancer tumor growth and metastasis by SREBP1-mediated HKDC1 expression. This provides a novel therapeutic strategy through targeting the PGC1β/HKDC1 signaling pathway for breast cancer treatment.

Objective: The objective of the present study was to meta-analyze relevant literature to gain a comprehensive understanding of the potential relationship between serum uric acid levels and risk of benign paroxysmal positional vertigo (BPPV).Methods: The databases of PubMed, Web of Science, Embase, Chinese National Knowledge Infrastructure, Wanfang, and SinoMed were systematically searched for observational case-control studies of the association between BPPV and serum uric acid levels published up to October 2018. Data from eligible studies were meta-analyzed using Stata 12.0.Results: A total of 12 studies were included in the analysis. There was a strong tendency for serum uric acid levels to be associated with risk of BPPV among studies conducted in China (OR 0.69, 95%CI 0.01–1.40, p = 0.053), but not among studies outside China (OR 1.07, 95%CI 1.08–3.22, p = 0.33). Across all studies, serum uric acid level was significantly higher among individuals with BPPV than among controls (OR 0.78, 95%CI 0.15–1.41, p = 0.015), yet it did not independently predict risk of the disorder (OR 1.003, 95%CI 0.995–1.012, p = 0.471).Conclusion: The available evidence suggests that BPPV is associated with elevated levels of serum uric acid, but these levels may not be an independent risk factor of BPPV.

Extranodal nasal-type natural killer/T-cell lymphoma (NKTCL) is an Epstein-Barr virus (EBV)-associated lymphoma with a strong tendency relapse or be refractory in response to chemotherapy. Development of a new strategy for NKTCL treatment is still quite necessary. In this study, we found that aspirin treatment suppresses VEGF expression in NKTCL SNK-6 cells. Further investigation showed that aspirin treatment increases histone methylation in the range of −100~0 that is proximal to the transcription start site on the VEGF promoter, subsequently decreasing the binding ability of Sp1 to the VEGF promoter with VEGF suppression. Furthermore, aspirin treatment modulates mitochondrial function with increased ROS formation and apoptosis in NKTCL cells. Aspirin treatment alone slightly inhibits NKTCL SNK-6 tumor growth and EBV replication; while in the presence of histone deacetylase inhibitor (HDACi) chidamide (CDM), aspirin significantly suppresses the VEGF signaling pathway with increased ROS overgeneration and EBV inhibition. We also showed that with the addition of chidamide, aspirin significantly suppresses NKTCL tumor growth in both in vitro cell culture and in vivo mouse model with prolonged mouse survival. This is the first time that the potential mechanism for aspirin-mediated VEGF suppression and anti-tumor effect has been discovered, and this study provides a new strategy for anti-tumor drug development for NKTCL treatment based on aspirin-mediated targeting of the VEGF signaling pathway and ROS formation.

We have previously reported that prenatal progestin exposure induces autism-like behavior in offspring through ERβ (estrogen receptor β) suppression in the brain, indicating that progestin may induce autism spectrum disorders (ASD). In this study, we aim to investigate whether prenatal progestin exposure is associated with ASD. A population-based case-control epidemiology study was conducted in Hainan province of China. The ASD children were first screened with the Autism Behavior Checklist (ABC) questionnaire, and then diagnosed by clinical professionals using the ASD diagnosis criteria found in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V). Eventually, 235 cases were identified as ASD from 37863 children aged 0–6 years old, and 682 matched control subjects with typically developing children were selected for the analysis of potential impact factors on ASD prevalence using multivariate logistic regression. Our data show that the ASD prevalence rate in Hainan was 0.62% with a boy:girl ratio of 5.4:1. Interestingly, we found that the following factors were strongly associated with ASD prevalence: use of progestin to prevent threatened abortion, use of progestin contraceptives at the time of conception, and prenatal consumption of progestin-contaminated seafood during the first trimester of pregnancy. All the above factors were directly or indirectly involved with prenatal progestin exposure. Additionally, we conducted in vivo experiments in rats to further confirm our findings. Either endogenous (progesterone) or synthetic progestin (norethindrone)-treated seafood zebrafish were used to feed pregnant dams, and the subsequent offspring showed autism-like behavior, which further demonstrated that prenatal progestin exposure may induce ASD. We conclude that prenatal progestin exposure may be associated with ASD development.