Fibroblast regulates angiogenesis in assembled oral cancer organoid: A possible role of NNMT.

OBJECTIVE: Tumour angiogenesis is affected by various cell types in the tumour microenvironment (TME), including cancer cells and cancer-associated fibroblasts (CAFs). Here, an assembled organoid model was generated to investigate the mechanism by which the TME regulates angiogenesis in oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: Secretion of vascular endothelial growth factor-A (VEGFA) was analysed to compare the proangiogenic properties of OSCC cells and corresponding CAFs. Cell aggregates consisting of endothelial cells (ECs), CAFs and cancer cells were generated to construct assembled organoids. Nicotinamide N-methyltransferase (NNMT) was pharmacologically or genetically inhibited to block the activation of CAFs. ATAC-seq was employed to test the transcriptional network of fibroblasts overexpressing NNMT. RESULTS: Compared with cancer cells, CAFs secreted more VEGFA. Coculture with CAFs more effectively promoted the sprouting of ECs. Blockade of CAF activation via inhibition of NNMT drastically reduced the expression of CD31 in the assembled organoids. Overexpression of NNMT enhanced the transcription of genes related to angiogenesis in fibroblasts. Specifically, NNMT orchestrated the enrichment of the transcription factor JUNB at the promoter of VEGFA. CONCLUSIONS: We clarify that stromal NNMT enables the steady reproduction of angiogenesis in assembled oral cancer organoids, providing a novel target for exploiting antiangiogenic therapy.

Influence of building spatial patterns on wind environment and air pollution dispersion inside an industrial park based on CFD simulation.

The "spatial pattern-wind environment-air pollution" within building clusters is closely interconnected, where different spatial pattern parameters may have varying degrees of impact on the wind environment and pollutant dispersion. Due to the complex spatial structure within industrial parks, this complexity may lead to the accumulation and retention of air pollutants within the parks. Therefore, to alleviate the air pollution situation in industrial parks in China and achieve the circular transformation and construction of parks, this study takes Hefei Circular Economy Demonstration Park as the research object. The microscale Fluent model in computational fluid dynamics (CFD) is used to finely simulate the wind flow field and the diffusion process of pollutants within the park. The study analyzes the triad relationship and influence mechanism of "spatial pattern-wind environment-air pollution" within the park and studies the influence of different spatial pattern parameters on the migration and diffusion of pollutants. The results show a significant negative correlation between the content of pollutants and wind speed inside the industrial park. The better the wind conditions, the higher the air quality. The spatial morphology parameters of the building complex are the main influences on the condition of its internal wind environment. Building coverage ratio and degree of enclosure have a significant negative correlation with wind conditions. Maintaining them near 0.23 and 0.37, respectively, is favorable to the quality of the surrounding environment. Moreover, the average height of the building is positively correlated with the wind environment condition. The rate of transport and dissipation of pollutants gradually increases as the average building height reaches 16 m. Therefore, a reasonable building planning strategy and arrangement layout can effectively improve the wind environment condition inside the park, thus alleviating the pollutant retention situation. The obtained results serve as a theoretical foundation for optimizing morphological structure design within urban industrial parks.

Oral microbiota imbalance: A predisposing factor for Henoch-Schönlein Purpura in children.

Oral microecological dysregulation has been shown to be associated with various immune system disorders. Henoch-schonlein purpura (HSP) is an autoimmune small vessel inflammatory disease in children of uncertain etiology, and studies have suggested that streptococcal infection may be an influential factor in its development. However, the relationship between oral microecological dysregulation and HSP has not been clearly studied so far. In this study, an epidemiological survey on the oral health status of children with HSP was investigated in this paper, and collected dental plaque from four groups of children for 16SrDNA high-throughput sequencing to analyze the composition and changes of oral microbial diversity among different groups. The results showed that the oral health status of children with HSP was poor, except for the incidence of caries in the 5-year-old group, the caries rate and dmfs/DMFS in the 3,4 and 5-year-old groups were higher than the same age in the fourth Chinese Oral Health Epidemiological Survey. Moreover, the development of HSP is accompanied by disturbances in the oral microbiota; a decrease in the number of Firmicutes which producing butyric acid may be closely associated with the development of HSP; changes in the abundance of Streptococcus and Neisseria may be a risk factor for the development of HSP.

Insulin resistance and dyslipidemia in low-birth-weight goat kids.

Low birth weight (LBW) impairs the development and health of livestock by affecting postnatal growth performance and metabolic health in adulthood. Previous studies on indigenous goats in southwest China showed that LBW goat kids had higher mortality and morbidity rates, including hepatic dyslipidemia and liver damage. However, the mechanism of insulin resistance affecting lipid metabolism under LBW conditions remains unclear. In this study, we conducted in vivo glucose-insulin metabolic studies, measured biochemical parameters, and analyzed related regulatory pathways. Both glucose tolerance tests and insulin tolerance tests indicated insulin resistance in LBW goat kids compared to controls (p < 0.05). The marker of insulin resistance, homeostasis model assessment (HOMA), was 2.85-fold higher in LBW than in control goats (p < 0.01). Additionally, elevated levels of free fatty acids in both plasma and skeletal muscle were observed in LBW goats compared to normal birth weight (NBW) goats (p < 0.05). Transcriptome analysis revealed impairments in lipid metabolism and insulin signaling in LBW goats. The observed lipid accumulation was associated with the upregulation of genes linked to fatty acid uptake and transport (FABP3), fatty acid oxidation (PPARA), triacylglycerol synthesis (LPIN1 and DGAT1), oxidative stress (ANKRD2), and insulin resistance (PGC1α). Furthermore, the insulin receptor substrate 2 (IRS2) was lower in the liver of LBW goat kids (p < 0.05). While there was no change in insulin function in skeletal muscle, LBW may lead to lipid accumulation in skeletal muscle by interfering with insulin function in the liver. These findings collectively impact the health and growth performance of livestock.

[Opening experiments: synthesis, purification, and characterization of polyethyleneimine-modified carbon dots].

Open experiments are an effective means of cultivating top-notch innovative talents. Based on student interests, research hotspots and our laboratory conditions, an experimental scheme was designed. In this experiment, polyethyleneimine modified carbon dots (PEI-CDs) were prepared via a one-step hydrothermal method using citric acid (CA) as the carbon source and PEI as the surface passivator. First, CA and PEI were completely dissolved in 0.1 mol/L HCl and transferred into an autoclave. The autoclave was heated to 130 ℃ for 2 h. PEI-CDs solution was obtained. After cooling to room temperature, the solution was concentrated to 2 mL by rotary evaporation. Finally, the PEI-CDs were precipitated, washed with ethanol, and dried under vacuum at 70 ℃ for 12 h. The obtained PEI-CDs were characterized by fluorescence spectrophotometry, absorption spectrophotometry, infrared spectrometry, and transmission electron microscopy. The results indicated that anhydrous-ethanol precipitation is a simple, rapid, economical, and green purification method. The as-prepared PEI-CDs had unique properties, such as good water solubility, high luminescence, uniform particle sizes, and good stability. Through this open experiment, students can not only master the operation of large-scale instruments but also enhance their interest in scientific research.

Dopamine promotes Klebsiella quasivariicola proliferation and inflammatory response in the presence of macrophages.

Background: Dopamine, a frequently used therapeutic agent for critically ill patients, has been shown to be implicated in clinical infections recently, however, the precise mechanisms underlying this association remain elusive. Klebsiella quasivariicola, a novel strain belonging to the Klebsiella species, exhibits potential pathogenic attributes. The impact of dopamine on K. quasivariicola infection has aroused our interest. Objective: Considering the contribution of host immune factors during infection, this study aimed to investigate the intricate interactions between K. quasivariicola, dopamine, and macrophages were explored. Methods: RAW264.7 cells and C57/BL6 mice were infected with K. quasivariicola, and the bacterial growth within macrophage, the production of inflammatory cytokines and the pathological changes in mice lungs were detected, in the absence or presence of dopamine. Results: Dopamine inhibited the growth of K. quasivariicola in the medium, but promoted bacterial growth when co-cultured with macrophages. The expression of proinflammatory cytokines increased in RAW 264.7 cells infected with K. quasivariicola, and a significant rise was observed upon the addition of dopamine. The infection of K. quasivariicola in mice induced an inflammatory response and lung injury, which were exacerbated by the administration of dopamine. Conclusions: Our findings suggest that dopamine may be one of the potential risk factors associated with K. quasivariicola infection. This empirical insight provides solid references for clinical precision medicine. Furthermore, an in vitro model of microbes-drugs-host immune cells for inhibitor screening was proposed to more accurately replicate the complex in vivo environment. This fundamental work had contributed to the present understanding of the crosstalk between pathogen, dopamine and host immune cells.

A Natural Casein-Based Separator with Brick-and-Mortar Structure for Stable, High-Rate Proton Batteries.

Rechargeable aqueous proton batteries with small organic molecule anodes are currently considered promising candidates for large-scale energy storage due to their low cost, stable safety, and environmental friendliness. However, the practical application is limited by the poor cycling stability caused by the shuttling of soluble organic molecules between electrodes. Herein, a cell separator is modified by a GO-casein-Cu2+ layer with a brick-and-mortar structure to inhibit the shuttling of small organic molecules. Experimental and calculation results indicate that, attributed to the synergistic effect of physical blocking of casein molecular chains and electrostatic and coordination interactions of Cu2+, bulk dissolution and shuttling of multiple small molecules can be inhibited simultaneously, while H+ transfer across the separators is not almost affected. With the protection of the GO-casein-Cu2+ separator, soluble small molecules, such as diquinoxalino[2,3-a:2',3'-c]phenazine,2,3,8,9,14,15-hexacyano (6CN-DQPZ) exhibit a high reversible capacity of 262.6 mA h g-1 and amazing stability (capacity retention of 92.9% after 1000 cycles at 1 A g-1). In addition, this strategy is also proved available to other active conjugated small molecules, such as indanthrone (IDT), providing a general green sustainable strategy for advancing the use of small organic molecule electrodes in proton cells.

Inadequate pregnancy-specific knowledge among patients with inflammatory bowel disease: A multicenter survey in China.

OBJECTIVES: The perceptions and attitudes of inflammatory bowel disease (IBD) patients towards pregnancy may affect their fertility plan and disease progression. We performed a nationwide multicenter survey of pregnancy-related knowledge among gastroenterologists and IBD patients in China to investigate whether specific educational interventions could improve their understanding and broadly influence fertility plan. METHODS: A cross-sectional questionnaire regarding pregnancy-specific knowledge was carried out among 63 IBD centers in China. Questionnaires were collected from 185 physicians and 609 patients. The patients then received education regarding pregnancy during IBD and filled in the same questionnaire again. Their knowledge regarding pregnancy during IBD was compared before and after education. RESULTS: Compared to physicians, patients' knowledge regarding fertility (39.1% vs 70.8%), imaging examinations (22.8% vs 72.4%), endoscopy performed during pregnancy (19.9% vs 71.4%), and vaccination for infants (16.6% vs 46.5%) was significantly more limited (all P < 0.001). There was a lack of knowledge among gastroenterologists regarding the delivery mode (36.8%), medications (36.8%), and emergency surgery (26.5%) during pregnancy in patients with IBD. After education, the patients showed significant improvement in knowledge regarding medications (26.7% vs 51.7%), fertility (45.0% vs 63.3%), heritability (40.0% vs 58.3%), indications for emergency surgery (15.0% vs 53.3%), imaging examinations during pregnancy (20.0% vs 40.0%), and vaccinations for infants (26.7% vs 45.0%) (all P < 0.05). CONCLUSIONS: Pregnancy-specific IBD knowledge needs to be improved among certain gastroenterologists and patients in China. Educational interventions can partially improve the knowledge levels of the patients.

Endoscopic submucosal dissection for the treatment of a large inflammatory fibroid polyp in the gastric antrum prolapsing into the duodenum: A case report.

RATIONALE: Inflammatory fibroid polyp (IFP), also known as Vanek tumor, is a rare, benign gastrointestinal lesion characterized by its inflammatory and fibroid histological features. IFP is often discovered incidentally during endoscopic examinations. It is exceedingly rare for an IFP to prolapse into the duodenum and results in incomplete obstruction of the pylorus. PATIENT CONCERNS: A 64-year-old male patient was admitted to the hospital with recurrent episodes of melena over a 6-month period, along with complaints of dizziness and fatigue in the past 10 days. DIAGNOSES: Gastroscopy showed a giant polypoid mass on the posterior wall of the gastric antrum, prolapsing into the duodenum. Abdominal computer tomography (CT) confirmed the tumor protruding into the duodenum. Pathologic examination of the resected specimen confirmed the IFP diagnosis. INTERVENTIONS: The giant tumor was completely and successfully excised using endoscopic submucosal dissection (ESD). After the surgery, the patient underwent acid suppression and fluid replenishment therapy. OUTCOMES: The patient responded well to ESD and was discharged in stable condition. As of the submission of the case report, there has been no recurrence of the tumor after a 5-month follow-up, and the patient is still under follow-up. LESSONS: While IFPs have traditionally been managed surgically, ESD demonstrates promising treatment outcomes, avoiding the need for surgical distal gastrectomy, and emerges as a safe and effective treatment option.

Evaluate the groundwater quality and human health risks for sustainable drinking and irrigation purposes in mountainous region of Chongqing, Southwest China.

Groundwater is crucial for agriculture and domestic consumption. This research investigated the hydrogeochemical properties and contaminant sources of groundwater within the mountainous terrain of northern Chongqing, with the objective of evaluating its appropriateness for irrigation and potable use. The hydrochemical type of the groundwater was HCO3 - Ca, dominated by silicate and calcite dissolutions. High NO3- (29.03% exceeds 10 mg/L) were attributed to the overuse of agricultural fertilizers. A comprehensive evaluation was conducted to determine the groundwater suitability for agricultural and potable uses. The results showed that groundwater in the southwestern region, particularly within the Yangtze River mainstem watershed, exhibited less suitability for irrigation owing to its lower mineralization, in contrast to the northeastern region near the Daning River watershed. But this trend is reversed for drinking purposes. Overall, the groundwater was appropriate for both drinking (93.55% were classified as excellent) and irrigation (70.98% were classified as low restriction) purposes in the study area. Deterministic and probabilistic noncarcinogenic health risk analyses centered on nitrate exposure revealed that infants (with 13.79% of samples >1) were at greater risk than children (8.58%), adult males (6.98%), and adult females (5.24%). This underscores the urgency to reduce nitrogen fertilizer usage and improve water management in the region. This research will provide guidance for the sustainable groundwater management in mountainous regions.

Deep and Durable Prostate-specific Antigen Response to Darolutamide with Androgen Deprivation Therapy and Docetaxel, and Association with Clinical Outcomes for Patients with High- or Low-volume Metastatic Hormone-sensitive Prostate Cancer: Analyses of the Randomized Phase 3 ARASENS Study.

BACKGROUND AND OBJECTIVE: Addition of darolutamide to androgen deprivation therapy (ADT) and docetaxel significantly improved overall survival (OS) in ARASENS (NCT02799602). Here we report on prostate-specific antigen (PSA) responses and their association with outcomes. METHODS: ARASENS is an international, double-blind, phase 3 study in patients with metastatic hormone-sensitive prostate cancer (mHSPC) randomized to darolutamide 600 mg orally twice daily (n = 651) or placebo (n = 654), both with ADT + docetaxel. The proportion of patients with undetectable PSA (<0.2 ng/ml) and time to PSA progression (≥25% relative and ≥2 ng/ml absolute increase from nadir) were compared between groups in prespecified exploratory analyses. PSA outcomes by disease volume and the association of undetectable PSA with OS and times to castration-resistant prostate cancer (CRPC) and PSA progression were assessed in post hoc analyses. KEY FINDINGS AND LIMITATIONS: The proportion of patients with undetectable PSA at any time was more than doubled with darolutamide versus placebo, at 67% versus 29% in the overall population, 62% versus 26% in the high-volume subgroup, and 84% versus 38% in the low-volume subgroup. Darolutamide delayed time to PSA progression versus placebo, with hazard ratios of 0.26 (95% confidence interval [CI] 0.21-0.31) in the overall population, 0.30 (95% CI 0.24-0.37) in the high-volume subgroup, and 0.093 (95% CI 0.047-0.18) in the low-volume subgroup. Undetectable PSA at 24 wk was associated with longer OS, with a hazard ratio of 0.49 (95% CI 0.37-0.65) in the darolutamide group, as well as longer times to CRPC and PSA progression, with similar findings in the disease volume subgroups. CONCLUSIONS AND CLINICAL IMPLICATIONS: Darolutamide + ADT + docetaxel led to deep and durable PSA responses in patients with high- or low-volume mHSPC. Achievement of undetectable PSA (<0.2 ng/ml) was correlated with better clinical outcomes. PATIENT SUMMARY: For patients with metastatic hormone-sensitive prostate cancer being treated with androgen deprivation therapy and docetaxel, PSA (prostate-specific antigen) became undetectable (below 0.2 ng/ml) in 67% of those also receiving darolutamide versus 29% of patients also receiving placebo. On average, patients achieving undetectable PSA lived longer than patients with detectable PSA.

Reward Circuit Local Field Potential Modulations Precede Risk Taking.

Risk taking behavior is a symptom of multiple neuropsychiatric disorders and often lacks effective treatments. Reward circuitry regions including the amygdala, orbitofrontal cortex, insula, and anterior cingulate have been implicated in risk-taking by neuroimaging studies. Electrophysiological activity associated with risk taking in these regions is not well understood in humans. Further characterizing the neural signalling that underlies risk-taking may provide therapeutic insight into disorders associated with risk-taking. Eleven patients with pharmacoresistant epilepsy who underwent stereotactic electroencephalography with electrodes in the amygdala, orbitofrontal cortex, insula, and/or anterior cingulate participated. Patients participated in a gambling task where they wagered on a visible playing card being higher than a hidden card, betting $5 or $20 on this outcome, while local field potentials were recorded from implanted electrodes. We used cluster-based permutation testing to identify reward prediction error signals by comparing oscillatory power following unexpected and expected rewards. We also used cluster-based permutation testing to compare power preceding high and low bets in high-risk (<50% chance of winning) trials and two-way ANOVA with bet and risk level to identify signals associated with risky, risk averse, and optimized decisions. We used linear mixed effects models to evaluate the relationship between reward prediction error and risky decision signals across trials, and a linear regression model for associations between risky decision signal power and Barratt Impulsiveness Scale scores for each patient. Reward prediction error signals were identified in the amygdala (p=0.0066), anterior cingulate (p=0.0092), and orbitofrontal cortex (p=6.0E-4, p=4.0E-4). Risky decisions were predicted by increased oscillatory power in high-gamma frequency range during card presentation in the orbitofrontal cortex (p=0.0022), and by increased power following bet cue presentation across the theta-to-beta range in the orbitofrontal cortex ( p =0.0022), high-gamma in the anterior cingulate ( p =0.0004), and high-gamma in the insula ( p =0.0014). Risk averse decisions were predicted by decreased orbitofrontal cortex gamma power ( p =2.0E-4). Optimized decisions that maximized earnings were preceded by decreases within the theta to beta range in orbitofrontal cortex ( p =2.0E-4), broad frequencies in amygdala ( p =2.0E-4), and theta to low-gamma in insula ( p =4.0E-4). Insula risky decision power was associated with orbitofrontal cortex high-gamma reward prediction error signal ( p =0.0048) and with patient impulsivity ( p =0.00478). Our findings identify and help characterize reward circuitry activity predictive of risk-taking in humans. These findings may serve as potential biomarkers to inform the development of novel treatment strategies such as closed loop neuromodulation for disorders of risk taking.

The effect of age, sex, and eastern cooperative oncology group performance status on the efficacy and safety of immune checkpoint inhibitors in patients with hepatocellular carcinoma: a systematic review and meta-analysis.

BACKGROUND: The effect of age, sex, and eastern cooperative oncology group performance status (ECOG PS) on the efficacy and safety of immune checkpoint inhibitor (ICI) therapy among hepatocellular carcinoma (HCC) patients remains elusive. Thus, a meta-analysis was conducted to evaluate whether such effects exist. RESEARCH DESIGN AND METHODS: Eligible studies in PubMed, Embase, and Cochrane Library databases were retrieved. RESULTS: One-hundred-and-eleven studies involving 14,768 HCC patients were included. The findings indicated that the ECOG PS didn't have a significant effect on the ORR and PFS in ICI-treated HCC patients (higher ECOG PS vs. lower ECOG PS: ORR: OR = 0.78, 95%CI = 0.55-1.10; PFS: HR = 1.15, 95%CI = 0.97-1.35), while those patients with a higher ECOG PS may have a worse OS (HR = 1.52, 95% CI = 1.26-1.84). There is no significant evidence of the effect of age (older vs. younger) or sex (males vs. females) on the efficacy of ICI therapy in HCC. CONCLUSION: ICI therapy in HCC should not be restricted strictly to certain patients in age or sex categories, while HCC patients with higher ECOG PS may require closer medication or follow-up strategy during ICI therapy. PROSPERO REGISTRATION: CRD42024518407.

Functional Oxidized Hyaluronic Acid Cross-Linked Decellularized Heart Valves for Improved Immunomodulation, Anti-Calcification, and Recellularization.

Tissue engineering heart valves (TEHVs) are expected to address the limitations of mechanical and bioprosthetic valves used in clinical practice. Decellularized heart valve (DHV) is an important scaffold of TEHVs due to its natural three-dimensional structure and bioactive extracellular matrix, but its mechanical properties and hemocompatibility are impaired. In this study, DHV is cross-linked with three different molecular weights of oxidized hyaluronic acid (OHA) by a Schiff base reaction and presented enhanced stability and hemocompatibility, which could be mediated by the molecular weight of OHA. Notably, DHV cross-linked with middle- and high-molecular-weight OHA could drive the macrophage polarization toward the M2 phenotype in vitro. Moreover, DHV cross-linked with middle-molecular-weight OHA scaffolds are further modified with RGD-PHSRN peptide (RPF-OHA/DHV) to block the residual aldehyde groups of the unreacted OHA. The results show that RPF-OHA/DHV not only exhibits anti-calcification properties, but also facilitates endothelial cell adhesion and proliferation in vitro. Furthermore, RPF-OHA/DHV shows excellent performance under an in vivo hemodynamic environment with favorable recellularization and immune regulation without calcification. The optimistic results demonstrate that OHA with different molecular weights has different cross-linking effects on DHV and that RPF-OHA/DHV scaffold with enhanced immune regulation, anti-calcification, and recellularization properties for clinical transformation.

The Outcomes of Patients with Omicron Variant Infection who Undergo Elective Surgery: A Propensity-score-matched Case-control Study.

Aim: To investigate whether it is safe for patients with Omicron variant infection to undergo surgery during perioperative period. Methods: A total of 3,661 surgical patients were enrolled: 3,081 who were not infected with the Omicron variant and 580 who were infected with the Omicron variant. We conducted propensity score matching (PSM) with a ratio of 1:4 and a caliper value of 0.1 to match the infected and uninfected groups based on 13 variables. After PSM, we further divided the Infected group (560 cases) by the number of days between the preoperative Omicron variant infection and surgery: 0-7, 8-14, 15-30, and >30 days. Multivariate logistic regression analysis was subsequently conducted on the categorical variables and continuous variables with a P value below 0.05, thereby comparing the infected group (0-7, 8-14, 15-30, >30 days) and the uninfected group for perioperative complications. Results: Multivariate logistic regression analysis revealed that, compared to the uninfected group, among the four subgroups of the infected patients (0-7, 8-14, 15-30, >30 days), only renal insufficiency in the 8-14 days subgroup (OR: 0.09, 95%CI 0.01-0.74, P = 0.025) and anemia in the > 30 days subgroup (OR 0.6, 95%CI 0.4-0.9, P < 0.017) showed significant difference. However, there was no statistically significant difference in the incidence rate of blood transfusion, postoperative intensive care unit transfer, lung infection/pneumonia, pleural effusion, atelectasis, respiratory failure, sepsis, postoperative deep vein thrombosis, hypoalbuminemia, urinary tract infections, and medical expenses. Conclusion: Omicron infection does not significantly increase the risk of perioperative major complications. The Omicron infection may not be a sufficient risk factor to postpone elective surgery.

A novel framework for high resolution air quality index prediction with interpretable artificial intelligence and uncertainties estimation.

Accurate air quality index (AQI) prediction is essential in environmental monitoring and management. Given that previous studies neglect the importance of uncertainty estimation and the necessity of constraining the output during prediction, we proposed a new hybrid model, namely TMSSICX, to forecast the AQI of multiple cities. Firstly, time-varying filtered based empirical mode decomposition (TVFEMD) was adopted to decompose the AQI sequence into multiple internal mode functions (IMF) components. Secondly, multi-scale fuzzy entropy (MFE) was applied to evaluate the complexity of each IMF component and clustered them into high and low-frequency portions. In addition, the high-frequency portion was secondarily decomposed by successive variational mode decomposition (SVMD) to reduce volatility. Then, six air pollutant concentrations, namely CO, SO2, PM2.5, PM10, O3, and NO2, were used as inputs. The secondary decomposition and preliminary portion were employed as the outputs for the bidirectional long short-term memory network optimized by the snake optimization algorithm (SOABiLSTM) and improved Catboost (ICatboost), respectively. Furthermore, extreme gradient boosting (XGBoost) was applied to ensemble each predicted sub-model to acquire the consequence. Ultimately, we introduced adaptive kernel density estimation (AKDE) for interval estimation. The empirical outcome indicated the TMSSICX model achieved the best performance among the other 23 models across all datasets. Moreover, implementing the XGBoost to ensemble each predicted sub-model led to an 8.73%, 8.94%, and 0.19% reduction in RMSE, compared to SVM. Additionally, by utilizing SHapley Additive exPlanations (SHAP) to assess the impact of the six pollutant concentrations on AQI, the results reveal that PM2.5 and PM10 had the most notable positive effects on the long-term trend of AQI. We hope this model can provide guidance for air quality management.

Regorafenib in Patients With Solid Tumors With BRAF Alterations: Results From the Targeted Agent and Profiling Utilization Registry (TAPUR) Study.

PURPOSE: Targeted Agent and Profiling Utilization Registry is a phase II basket trial evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancer with genomic alterations known to be drug targets. Results of a cohort of patients with solid tumors with BRAF alterations treated with regorafenib are reported. METHODS: Eligible patients had measurable disease (RECIST v.1.1), Eastern Cooperative Oncology Group performance status 0-1, adequate organ function, and no standard treatment options. The primary end point was disease control (DC), defined as investigator assessment of patients with complete or partial response (PR) or stable disease of at least 16-weeks duration (SD16+). Low accruing histology-specific cohorts with BRAF alterations treated with regorafenib were collapsed into a single histology-pooled cohort for this analysis. The results were evaluated on the basis of a one-sided exact binomial test with a null DC rate of 15% versus 35% (power, 0.84; α, .10). Secondary end points were objective response (OR), progression-free survival, overall survival, duration of response, duration of stable disease, and safety. RESULTS: Twenty-eight patients with 12 tumor types with BRAF alterations were enrolled from June 2016 to June 2021. All patients were evaluable for efficacy. Two patients with PR and four with SD16+ were observed for DC and OR rates of 21% (90% CI, 12 to 100) and 7% (95% CI, 1 to 24), respectively. The null hypothesis of 15% DC rate was not rejected (P = .24). Eight patients had at least one grade 3 adverse event or serious adverse event at least possibly related to regorafenib. CONCLUSION: Regorafenib did not meet prespecified criteria to declare a signal of activity in patients with solid tumors with BRAF alterations.

Detection of lung cancer through SERS analysis of serum.

Early detection and postoperative assessment are crucial for improving overall survival among lung cancer patients. Here, we report a non-invasive technique that integrates Raman spectroscopy with machine learning for the detection of lung cancer. The study encompassed 88 postoperative lung cancer patients, 73 non-surgical lung cancer patients, and 68 healthy subjects. The primary aim was to explore variations in serum metabolism across these cohorts. Comparative analysis of average Raman spectra was conducted, while principal component analysis was employed for data visualization. Subsequently, the augmented dataset was used to train convolutional neural networks (CNN) and Resnet models, leading to the development of a diagnostic framework. The CNN model exhibited superior performance, as verified by the receiver operating characteristic curve. Notably, postoperative patients demonstrated an increased likelihood of recurrence, emphasizing the crucial need for continuous postoperative monitoring. In summary, the integration of Raman spectroscopy with CNN-based classification shows potential for early detection and postoperative assessment of lung cancer.

Tracing the impacts of ecological water replenishment on the sources and transformation of groundwater nitrate through isotope and microbial analysis.

Ecological water replenishment (EWR) changes the recharge conditions, flow fields, and physicochemical properties of regional groundwater. However, the resulting impacts on mechanisms regulating the sources and transformation of groundwater nitrate remain unclear. This study investigated how EWR influences the sources and transformation processes of groundwater nitrate using an integrated approach of Water chemistry analysis and stable isotopes (δ15N-NO3- and δ18O-NO3-) along with microbial techniques. The results showed that groundwater NO3-N decreased from 12.98 ± 7.39 mg/L to 7.04 ± 8.52 mg/L after EWR. Water chemistry and isotopic characterization suggested that groundwater nitrate mainly originated from sewage and manure. The Bayesian isotope mixing model (MixSIAR) indicated that EWR increased the average contribution of sewage and manure sources to groundwater nitrate from 46 % to 61 %, whereas that of sources of chemical fertilizer decreased from 43 % to 21 %. Microbial community analysis revealed that EWR resulted in a substantial decrease in the relative abundance of Pseudomonas spp denitrificans, from 13.7 % to 0.6 %. Both water chemistry and microbial analysis indicated that EWR weakened denitrification and enhanced nitrification in groundwater. EWR increases the contribution of nitrate to groundwater by promoting the release of sewage and feces in the unsaturated zone. However, the dilution effect caused by EWR was stronger than the contribution of sewage and fecal sources to groundwater nitrate. As a result, EWR helped to reduce groundwater nitrate concentrations. This study showed the effectiveness of integrated isotope and microbial techniques for delineating the sources and transformations of groundwater nitrate influenced by EWR.

Feedback regulation of the isoprenoid pathway by SsdTPS overexpression has the potential to enhance plant tolerance to drought stress.

In order to maintain the dynamic physiological balance, plants are compelled to adjust their energy metabolism and signal transduction to cope with the abiotic stresses caused by complex and changeable environments. The diterpenoid natural compound and secondary metabolites, sclareol, derived from Salvia sclarea, has gained significant attention owing to its economic value as a spice material and diverse physiological activities. Here, we focused on the roles and regulatory mechanisms of the sclareol diterpene synthase gene SsdTPS in the resistance of S. sclarea to abiotic stresses. Our results suggested that abiotic stresses could induce the response and upregulation of SsdTPS expression and isoprenoid pathway in S. sclarea. Ectopic expression of SsdTPS conferred drought tolerance in transgenic Arabidopsis, compared with wild-type. Overexpression of SsdTPS enhanced the transcription of ABA signal transduction synthetic regulators and induced the positive feedback upregulating key regulatory genes in the MEP pathway, thereby promoting the increase of ABA content and improving drought tolerance in transgenic plants. In addition, SsdTPS-overexpressed transgenic Arabidopsis improved the responses of stomatal regulatory genes and ROS scavenging enzyme activities and gene expression to drought stress. This promoted the stomatal closure and ROS reduction, thus enhancing water retention capacity and reducing oxidative stress damage. These findings unveil the potentially positive role of SsdTPS in orchestrating multiple regulatory mechanisms and maintaining homeostasis for improved abiotic stress resistance in S. sclarea, providing a novel insight into strategies for promoting drought resistance and cultivating highly tolerant plants.