Early detection and stratification of colorectal cancer using plasma cell-free DNA fragmentomic profiling.

Timely accurate and cost-efficient detection of colorectal cancer (CRC) is of great clinical importance. This study aims to establish prediction models for detecting CRC using plasma cell-free DNA (cfDNA) fragmentomic features. Whole-genome sequencing (WGS) was performed on cfDNA from 620 participants, including healthy individuals, patients with benign colorectal diseases and CRC patients. Using WGS data, three machine learning methods were compared to build prediction models for the stratification of CRC patients. The optimal model to discriminate CRC patients of all stages from healthy individuals achieved a sensitivity of 92.31% and a specificity of 91.14%, while the model to separate early-stage CRC patients (stage 0-II) from healthy individuals achieved a sensitivity of 88.8% and a specificity of 96.2%. Additionally, the cfDNA fragmentation profiles reflected disease-specific genomic alterations in CRC. Overall, this study suggests that cfDNA fragmentation profiles may potentially become a noninvasive approach for the detection and stratification of CRC.

Neurotransmitter system gene variants as biomarkers for the therapeutic efficacy of rTMS and SSRIs in obsessive-compulsive disorder.

Purpose: This study aims to examine the potential influence of RS4680 (COMT), RS16965628 (SLC6A4), and RS1019385 (GRIN2B) polymorphisms on the therapeutic response to repetitive transcranial magnetic stimulation (rTMS) and selective serotonin reuptake inhibitors (SSRIs) in individuals with obsessive-compulsive disorder (OCD). Patients and methods: Thirty-six untreated outpatients diagnosed with OCD were recruited and allocated to active or sham rTMS groups for two weeks. The mean age of the participants was 31.61, with 17 males (47.22%) and 19 females (52.78%). Peripheral blood samples (5 mL) were collected from each participant using ethylenediaminetetraacetic acid (EDTA) vacuum tubes for genotyping purposes, clinical evaluation was taken place at baseline and second week. Results: The A allele of RS4680, C allele of RS16965628, and GG allele of RS1019385 were identified as potential bio-markers for predicting treatment response to OCD treatments (rTMS & SSRIs). Conclusion: Those genes may serve as bio-markers for the combined treatment of rTMS and SSRIs in OCD. The finding hold promise for further research and the potential implementation of precision treatment of OCD. Clinical trial registration: https://www.chictr.org.cn, identifier ChiCTR1900023641.

Retrosynthesis Zero: Self-Improving Global Synthesis Planning Using Reinforcement Learning.

The field of computer-aided synthesis planning (CASP) has witnessed significant growth in recent years. Still, many CASP programs rely on large data sets to train neural networks, resulting in limitations due to the data quality and prior knowledge from chemists. In response, we propose Retrosynthesis Zero (ReSynZ), a reaction template-based method that combines Monte Carlo Tree Search with reinforcement learning inspired by AlphaGo Zero. Unlike other single-step reaction template-based CASP methods, ReSynZ takes complete synthesis paths for complex molecules, determined by reaction rules, as input for training the neural network. ReSynZ enables neural networks trained with relatively small reaction data sets (tens of thousands of data) to generate multiple synthesis pathways for a target molecule and suggest possible reaction conditions. On multiple data sets of molecular retrosynthesis, ReSynZ demonstrates excellent predictive performance compared to existing algorithms. The advantages, such as self-improving model features, flexible reward settings, the potential to surpass human limitations in chemical synthesis route planning, and others, make ReSynZ a valuable tool in chemical synthesis design.

Evaluation of Molecular Residual Disease by a Fixed Panel in Resectable Colorectal Cancer.

Purpose: Molecular residual disease (MRD) is a promising biomarker in colorectal cancer (CRC) for prognosis and guiding treatment, while the whole-exome sequencing (WES) based tumor-informed assay is standard for evaluating MRD based on circulating tumor DNA (ctDNA). In this study, we assessed the feasibility of a fixed-panel for evaluating MRD in CRC. Materials and Methods: 75 patients with resectable stage I-III CRC were enrolled. Tumor tissues obtained by surgery, and pre-operative and post-operative day 7 blood samples were collected. The ctDNA was evaluated using the tumor-agnostic and tumor-informed fixed assays, as well as the WES-based and panel-based personalized assays in randomly selected patients. Results: The tumor-informed fixed assay had a higher pre-operative positive rate than the tumor-agnostic assay (73.3% vs 57.3%). The pre-op ctDNA status failed to predict disease-free survival (DFS) in either of the fixed assays, while the tumor-informed fixed assay-determined post-op ctDNA positivity was significantly associated with worse DFS (HR, 20.74, 95%CI 7.19-59.83; p<0.001), which was an independent predictor by multivariable analysis (HR, 28.57, 95%CI 7.10-114.9; p<0.001). Sub-cohort analysis indicated the WES-based personalized assay had the highest pre-operative positive rate (95.1%). The two personalized assays and the tumor-informed fixed assay demonstrated same results in post-op landmark (HR, 26.34, 95%CI, 6.01-115.57; p<0.001), outperforming the tumor-agnostic fixed panel (HR, 3.04, 95%CI, 0.94-9.89; p=0.052). Conclusion: Our study confirmed the prognostic value of the ctDNA positivity at post-op day 7 by the tumor-informed fixed panel. The tumor-informed fixed panel may be a cost-effective method to evaluate MRD, which warrants further studies in future.

Occurrence, source apportionment and ecological risk of bisphenol analogues in river sediments in areas with different land use patterns.

Bisphenol analogues (BPs) have gained increasing attention in recent years due to their ubiquitousness and potential endocrine disrupting properties in environments. However, little information is available on their spatiotemporal distribution, source apportionment and ecological risk in river sediments, especially the case in river basins with a high population density and those typical regions with agricultural-urban gradient, where land use patterns and intensity of human activity are varying. In this study, field investigations of BPs in the sediment of the entire Qinhuai River Basin, a typical agricultural-suburban agricultural-urban gradient area, were conducted before and after the flood period. Thirty-two sites were sampled for six types of BPs, resulted in no significant difference in the concentration of ΣBPs between the two periods, with ΣBPs ranging from 3.92 to 151 ng/g and 2.16-59.0 ng/g, respectively. Bisphenol A (BPA) was the main contributor. Whereas a multivariate analysis of variance (MANOVA) suggested that the composition structure of BPs had been influenced by water periods. The land use patterns had an impact on the distribution of ΣBPs in river sediments, which was more significant in after the flood period, with ΣBPs in urban rivers was 1.85 times, 3.44 times, and 3.08 times higher than the suburban rivers, agricultural rivers, and reservoirs, respectively. Yet land use types did not significantly alter the composition structure of BPs. The correlation analysis between BPs and the physicochemical properties of sediments showed a significant positive correlation between BPA and total organic carbon (TOC). The positive matrix factorization model (PMF) suggested that BPs in sediments of the basin might be influenced by industrial coatings, textiles, electronics and biopharmaceuticals, as well as urban wastewater or solid waste generated from daily life. The ecological risk assessment posed by BPA, based on the risk quotient, indicated that the ecological risk of BPA in sediments was low for three indicator benthic organisms: crustaceans, worms, and mollusks. However, the risk of BPA in river sediments varied among different land use patterns, with the risk ranking as follows: reservoirs < agricultural rivers < suburban rivers < urban rivers.

Palladium-Catalyzed Ligand-Controlled Switchable Hetero-(5 + 3)/Enantioselective [2σ+2σ] Cycloadditions of Bicyclobutanes with Vinyl Oxiranes.

For nearly 60 years, significant research efforts have been focused on developing strategies for the cycloaddition of bicyclobutanes (BCBs). However, higher-order cycloaddition and catalytic asymmetric cycloaddition of BCBs have been long-standing formidable challenges. Here, we report Pd-catalyzed ligand-controlled, tunable cycloadditions for the divergent synthesis of bridged bicyclic frameworks. The dppb ligand facilitates the formal (5+3) cycloaddition of BCBs and vinyl oxiranes, yielding valuable eight-membered ethers with bridged bicyclic scaffolds in 100% regioselectivity. The Cy-DPEphos ligand promotes selective hetero-[2σ+2σ] cycloadditions to access pharmacologically important 2-oxabicyclo[3.1.1]heptane (O-BCHeps). Furthermore, the corresponding catalytic asymmetric synthesis of O-BCHeps with 94-99% ee has been achieved using chiral (S)-DTBM-Segphos, representing the first catalytic asymmetric cross-dimerization of two strained rings. The obtained O-BCHeps are promising bioisosteres for ortho-substituted benzenes.

Switching between the [2π+2σ] and Hetero-[4π+2σ] Cycloaddition Reactivity of Bicyclobutanes with Lewis Acid Catalysts Enables the Synthesis of Spirocycles and Bridged Heterocycles.

The exploration of the complex chemical diversity of bicyclo[n.1.1]alkanes and their use as benzene bioisosteres has garnered significant attention over the past two decades. Regiodivergent syntheses of thiabicyclo[4.1.1]octanes (S-BCOs) and highly substituted bicyclo[2.1.1]hexanes (BCHs) using a Lewis acid-catalyzed formal cycloaddition of bicyclobutanes (BCBs) and 3-benzylideneindoline-2-thione derivatives have been established. The first hetero-(4+3) cycloaddition of BCBs, catalyzed by Zn(OTf)2, was achieved with a broad substrate scope under mild conditions. In contrast, the less electrophilic BCB ester undergoes a Sc(OTf)3-catalyzed [2π+2σ] reaction with 1,1,2-trisubstituted alkenes, yielding BCHs with a spirocyclic quaternary carbon center. Control experiments and preliminary theoretical calculations suggest that the diastereoselective [2π+2σ] product formation may involve a concerted cycloaddition between a zwitterionic intermediate and E-1,1,2-trisubstituted alkenes. Additionally, the hetero-(4+3) cycloaddition may involve a concerted nucleophilic ring-opening mechanism.

Objective Quantification Technique and Widely Targeted Metabolomics-Based Analysis of the Effects of Different Saccharidation Processes on Preserved French Plums.

Vacuum saccharification significantly affected the flavor and color of preserved French plums. However, the correlation between color, flavor, and metabolites remains unclear. Metabolites contribute significantly to enhancing the taste and overall quality of preserved French plums. This study aimed to investigate the distinctive metabolites in samples from various stages of the processing of preserved French plums. The PCF4 exhibited the highest appearance, overall taste, and chroma. Furthermore, utilizing UPLC and ESI-Q TRAP-MS/MS, a comprehensive examination of the metabolome in the processing of preserved French plums was conducted. A total of 1776 metabolites were analyzed. Using WGCNA, we explored metabolites associated with sensory features through 10 modules. Based on this, building the correlation of modules and objective quantification metrics yielded three key modules. After screening for 151 differentiated metabolites, amino acids, and their derivatives, phenolic acids, flavonoids, organic acids, and other groups were identified as key differentiators. The response of differential metabolites to stress influenced the taste and color properties of preserved prunes. Based on these analyses, six important metabolic pathways were identified. This study identified changes in the sensory properties of sugar-stained preserved prunes and their association with metabolite composition, providing a scientific basis for future work to improve the quality of prune processing.

New insights into the interplay between autophagy, gut microbiota and insulin resistance in metabolic syndrome.

Metabolic syndrome (MetS) is a widespread and multifactorial disorder, and the study of its pathogenesis and treatment remains challenging. Autophagy, an intracellular degradation system that maintains cellular renewal and homeostasis, is essential for maintaining antimicrobial defense, preserving epithelial barrier integrity, promoting mucosal immune response, maintaining intestinal homeostasis, and regulating gut microbiota and microbial metabolites. Dysfunctional autophagy is implicated in the pathological mechanisms of MetS, involving insulin resistance (IR), chronic inflammation, oxidative stress, and endoplasmic reticulum (ER) stress, with IR being a predominant feature. The study of autophagy represents a valuable field of research with significant clinical implications for identifying autophagy-related signals, pathways, mechanisms, and treatment options for MetS. Given the multifactorial etiology and various potential risk factors, it is imperative to explore the interplay between autophagy and gut microbiota in MetS more thoroughly. This will facilitate the elucidation of new mechanisms underlying the crosstalk among autophagy, gut microbiota, and MetS, thereby providing new insights into the diagnosis and treatment of MetS.

Divergent Synthesis of Sulfur-Containing Bridged Cyclobutanes by Lewis Acid Catalyzed Formal Cycloadditions of Pyridinium 1,4-Zwitterionic Thiolates and Bicyclobutanes.

Bridged cyclobutanes and sulfur heterocycles are currently under intense investigation as building blocks for pharmaceutical drug design. Two formal cycloaddition modes involving bicyclobutanes (BCBs) and pyridinium 1,4-zwitterionic thiolate derivatives were described to rapidly expand the chemical space of sulfur-containing bridged cyclobutanes. By using Ni(ClO4)2 as the catalyst, an uncommon higher-order (5+3) cycloaddition of BCBs with quinolinium 1,4-zwitterionic thiolate was achieved with broad substrate scope under mild reaction conditions. Furthermore, the first Lewis acid-catalyzed asymmetric polar (5+3) cycloaddition of BCB with pyridazinium 1,4-zwitterionic thiolate was accomplished. In contrast, pyridinium 1,4-zwitterionic thiolates undergo an Sc(OTf)3-catalyzed formal (3+3) reaction with BCBs to generate thia-norpinene products, which represent the initial instance of synthesizing 2-thiabicyclo[3.1.1]heptanes (thia-BCHeps) from BCBs. Moreover, we have successfully used this (3+3) protocol to rapidly prepare thia-BCHeps-substituted analogues of the bioactive molecule Pitofenone. Density functional theory (DFT) computations imply that kinetic factors govern the (5+3) cycloaddition reaction between BCB and quinolinium 1,4-zwitterionic thiolate, whereas the (3+3) reaction involving pyridinium 1,4-zwitterionic thiolates is under thermodynamic control.

A 15-Inflammation-Related Gene Signature Predicts the Prognosis of Patients With Pancreatic Ductal Adenocarcinoma.

Chronic inflammation promotes the development of pancreatic ductal adenocarcinoma (PDAC) and PDAC-related inflammatory tumor microenvironment facilitates tumor growth and metastasis. Thus, we aimed to study the association between inflammatory response and prognosis in patients with PDAC. We conducted the whole transcriptomic sequencing using tissue samples collected from patients diagnosed with PDAC (n = 106) recruited from Shandong Cancer Hospital. We first constructed a prognostic signature using 15 inflammation-related genes in The Cancer Genome Atlas (TCGA) cohort (n = 177) and further validated it in an independent International Cancer Genome Consortium (ICGC) cohort (n = 90) and our in-house cohort. PDAC patients with a higher risk score had poorer overall survival (OS) (P < 0.001; HR, 3.02; 95% CI, 1.94-4.70). The association between the prognostic signature and OS remained significant in the multivariable Cox regression adjusting for age, sex, alcohol exposure, diabetes, and stage (P < 0.001; HR, 2.91; 95% CI, 1.73-4.89). This gene signature also robustly predicted prognosis in the ICGC cohort (P = 0.01; HR, 1.94; 95% CI, 1.14-3.30) and our cohort (P < 0.001; HR, 2.40; 95% CI, 1.45-3.97). Immune subtype C3 (inflammatory) was enriched and CD8+ T cells were higher in patients with a lower risk score (P < 0.05). Furthermore, PDAC patients with higher risk scores were more sensitive to chemotherapy, immunotherapy, and PARP inhibitors (P < 0.05). In sum, we identified a novel gene signature that was associated with inflammatory response for risk stratification, prognosis prediction, and therapy guidance in PDAC patients. Future studies are warranted to validate the clinical utility of the signature.

New findings on CD16brightCD62Ldim neutrophil subtypes in sepsis-associated ARDS: an observational clinical study.

Background: The CD16brightCD62Ldim neutrophil subtype is a recently identified neutrophil subtype. The aim of this study was to evaluate changes of peripheral blood CD16brightCD62Ldim neutrophils in patients with sepsis-associated ARDS. Methods: We prospectively recruited adult patients with sepsis-associated ARDS in the intensive care unit (ICU). Patient demographic data, medical history information, and laboratory data were collected within 48 hours of enrollment, and flow cytometry was applied to analyze the CD16brightCD62Ldim neutrophil subtype in the patients' peripheral blood. Multifactor COX regression models were used to analyze factors affecting prognosis, and Spearman correlation coefficients were used to analyze clinical and laboratory indicators affecting complications of infection. Results: Of the 40 patients, 9 patients died by the 28-day follow-up, indicating a mortality rate of 22.5%. Patients in the nonsurvival group had higher CD16brightCD62Ldim neutrophil levels. Patients with sepsis-associated ARDS who had a baseline proportion of CD16brightCD62Ldim neutrophil subtypes to total neutrophils in peripheral blood >3.73% had significantly higher 28-day mortality, while patients with CD16brightCD62Ldim neutrophil subtypes counts >2.62×109/L were also associated with significantly higher 28-day mortality. The percentage of the CD16brightCD62Ldim neutrophil subtype (HR=5.305, 95% CI 1.986-14.165, p=0.001) and IL-8 (HR=3.852, 95% CI 1.561-9.508, p=0.003) were independent risk factors for the development of infectious complications in patients with sepsis-related ARDS. The percentage of CD16brightCD62Ldim neutrophil subtypes predicted an AUC of 0.806 (95% CI 0.147-0.964, P=0.003) for the development of infectious complications, and 0.742 (95% CI 0.589-0.895, P=0.029) for the prediction of death within 28 days. Conclusion: We identified for the first time that CD16brightCD62Ldim neutrophils are elevated in patients with sepsis-associated ARDS and are associated with infectious complications and poor prognosis. The percentage of CD16brightCD62Ldim neutrophil subtypes may serve as a predictor of the development of infectious complications in patients with ARDS.

Investigating the regional ecological environment stability and its feedback effect on interference using a novel vegetation resilience assessment model.

Vegetation resilience is critical for understanding the dynamic feedback effect of regional ecological environment stability against interferences. Thus, based on quantify the interferences of climate dryness and vegetation water deficit affecting vegetation growth function, incorporate mechanical Hooke's law to develop a vegetation resilience assessment model by quantitatively expressing vegetation growth function maintenance ability, to reveal the ecological environment stability and its feedback effect on interferences in the study area. The essential discoveries of the study are as follows: (1) with the increase of precipitation and the improvement of afforestation on soil erosion, the interferences intensity of climate dryness and vegetation water deficit in the ecological environment decreased by 5.88 % and 4.92 % respectively, the regional vegetation growth function loss was improved, especially in the southern region; (2) the decrease of vegetation growth function loss promoted the vegetation resilience level fluctuated from class II to class IV, with the average annual vegetation resilience increased by 7.02 %, reflecting that the regional ecological environment stability increased from difficult to rapid recovery after disturbance, and the benefit was especially noticeable in the eastern and southern forested areas; (3) the contribution rates of climate dryness and vegetation water deficit to the variation of vegetation resilience caused by vegetation restoration were -1.38 % and 4.73 %, respectively, and the prominent positive feedback effect of increasing vegetation resilience with decreasing vegetation water deficit degree in forest restoration area, indicating that the vegetation water deficit greatly impacts ecological environment stability in the study area, and forest restoration constantly improves regional ecological environment stability more than grassland restoration. This research has crucial guiding implications for supporting the sustainable development of regional ecological environments.

Semirational Design Strategy To Enhance the Thermostability and Catalytic Activity of Cytochrome P450 105D7 for the Degradation of the Pharmaceutically Active Compounds: Diclofenac.

Pharmaceutically active compounds are an important category of emerging pollutants, and their biological transformation processes in the environment are crucial for understanding and evaluating the migration, transformation, and environmental fate of emerging pollutants. The cytochrome P450 105 enzyme family has been proven to play an important role in the degradation of exogenous environmental pollutants. However, its thermostability and catalytic activity still need to be improved to better adapt to complex environmental conditions. This work elucidates the key mechanisms and important residues of the degradation reaction through multiple computational strategies, establishes a mutation library, and obtains 21 single-point mutation designs. Experimental verification showed that 16 single mutants had enhanced thermostability, with the R89F and L197Y mutants showing the highest increases in thermostability at 135 and 119% relative to the wild-type enzyme, respectively. Additionally, as a result of the higher specific activity of D390Q, it was selected for combination mutagenesis, ultimately resulting in three combination mutants (R89F/L197Y, R89F/D390Q, and R89F/L197Y/D390Q) with enhanced thermostability and catalytic activity. This study provides a modification approach for constructing efficient enzyme variants through semirational design and can contribute to the development of control technologies for emerging pollutants.

The Role of Metabolomics and Microbiology in Urinary Tract Infection.

One of the common illnesses that affect women's physical and mental health is urinary tract infection (UTI). The disappointing results of empirical anti-infective treatment and the lengthy time required for urine bacterial culture are two issues. Antibiotic misuse is common, especially in females who experience recurrent UTI (rUTI). This leads to a higher prevalence of antibiotic resistance in the microorganisms that cause the infection. Antibiotic therapy will face major challenges in the future, prompting clinicians to update their practices. New testing techniques are making the potential association between the urogenital microbiota and UTIs increasingly apparent. Monitoring changes in female urinary tract (UT) microbiota, as well as metabolites, may be useful in exploring newer preventive treatments for UTIs. This review focuses on advances in urogenital microbiology and organismal metabolites relevant to the identification and handling of UTIs in an attempt to provide novel methods for the identification and management of infections of the UT. Particular attention is paid to the microbiota and metabolites in the patient's urine in relation to their role in supporting host health.

Improvement of evapotranspiration simulation study in the Hailar River basin under the influence of vegetation dynamics.

In arid and semi-arid areas with <400 mm of precipitation, evapotranspiration (ET) accounts for about 80% of precipitation and is the main water consumer in the watershed. However, vegetation greening in recent years will increase ET and exacerbate the aridity of the area by affecting soil moisture in the root system. Vegetation changes are regional and spatially heterogeneous, therefore, in order to characterize ET changes under vegetation dynamics, it is necessary to expand the spatial scale of ET simulation. However, widely used evapotranspiration simulation models, such as the Shuttleworth-Wallace model (SW model), are deficient in reflecting the direct and indirect effects of vertical (i.e., soil depths) and horizontal (i.e., vegetation dynamics) directions. Based on field sampling and constructed structural equation model (SEM), we found that vegetation dynamics affect evapotranspiration not only directly, but also indirectly by affecting soil moisture at different depths. On this basis, we defined the weighting coefficients of 0.85 and 0.15 for grassland vegetation zones, 0.3, 0.15, 0.20, 0.25, 0.10 for forest-grass interspersed zones, and 0.20, 0.55, 0.25 for forested zones, respectively, based on the SEM results. Different soil moisture weighting coefficients were defined within different vegetation type zones and the improved SW model is called S-W-α. Comparing the simulation results with the measured data, S-W-α improved the ET simulation accuracy in this region by 33.92% and the improved ET spatial trend can respond to the dynamic changes of vegetation. Replacing the ET module in the Block-wise use of TOPMODEL and Muskingum-Cunge method mode (BTOP model) with the modified S-W-α, the results show that the simulation accuracy of the improved model is increased by 25%, and the Nash is higher than 75% for both the rate period and the validation period, which realizes the extension of the model from the point scale to the basin scale. The modified model may provide technical support for simulation of evapotranspiration and management of ecosystem health in ecologically fragile areas.

Prognostic factors for postoperative papillary thyroid cancer with unexplained elevated Tg: A retrospective study.

Objective: This study aimed to investigate the underlying reasons for unexplained elevated thyroglobulin (Tg) in postoperative papillary thyroid cancer (PTC) patients according to follow-up results post RAT and to explore the long-term clinical outcomes and prognostic factors associated with these patients. Methods: From April 2016 to June 2019, a retrospective study was conducted on postoperative PTC patients who underwent RAT at our institution. Patients with preablative stimulated thyroglobulin (psTg) > 10 ng/mL but no structurally evident disease were enrolled. The causal categorization for elevated Tg was analyzed 6 months post RAT and the long-term therapeutic responses were assessed at the end of follow-up. To identify risk factors influencing recurrence-free survival (RFS), both univariate and multivariate Cox regression analysis were employed. Kaplan-Meier method was utilized for plotting survival curves. Results: A cohort of 165 subjects was enrolled for the analyses. Based on the results of a six-month follow-up, the postoperative unexplained elevated Tg among 165 patients could be ultimately attributed to thyroid remnant in 13.94% (23/165), biochemical disease in 60.00% (99/165), and structural disease in 26.06% (43/165). With a median follow-up of 58 months, 51 (30.91%), 34 (20.60%), 21 (12.73%), and 59 (35.76%) of the 165 patients achieved ER, IDR, BIR and SIR, respectively. Univariate analysis showed that N stage, TNM stage and suppressed Tg 6 months post RAT may be prognostic factors affecting RFS. Multivariate analysis showed that N1b stage [HR:2.749, P = 0.003] and II/III stage [HR:2.910, P = 0.001] were independent risk factors for RFS. Conclusion: The proportion of 165 postoperative PTC patients with unexplained elevated Tg developing structural disease within nearly 5 years was over 30%. Patients with N1b stage and higher TNM stage were more likely to develop structural disease.

Large-scale causal analysis of gut microbiota and six common complications of diabetes: a mendelian randomization study.

BACKGROUND: This study aimed to reveal the association between the gut microbiota (GM) and six diabetic complications: diabetic hypoglycemia; ketoacidosis; nephropathy; neuropathy; retinopathy; and Charcot's foot. METHODS: GM data were obtained from the MiBioGen consortium and Dutch Microbiome Project while data on the six diabetic complications were obtained from the FinnGen consortium. Two-sample Mendelian randomization (TSMR) was performed to explore the association between GM and the common diabetic complications. Inverse MR analysis was conducted to examine the effect of diabetic complications on the identified GM. Sensitivity tests were conducted to validate the stability of the results. Finally, multivariate MR (MVMR) was performed to determine whether GM had a direct influence on the diabetic complications. RESULTS: After multiple corrections, the inverse variance weighted (IVW) results predicted 61 suggestive markers between GM and six diabetic complications. In particular, the IVW results revealed that the Bacteroidia class and Bacteroidales order were positively associated with diabetic hypoglycemia while the Verrucomicrobiae class and Verrucomicrobiales order were positively associated with diabetic nephropathy. Based on the replication analysis, these results were identified to be stable. MVMR showed that the results remained stable after accounting for traditional risk factors. CONCLUSION: Extensive causal associations were found between GM and diabetic complications, which may provide new insights into the mechanisms of microbiome-mediated complications of diabetes.

MAEL in human cancers and implications in prognostication and predicting benefit from immunotherapy over VEGFR/mTOR inhibitors in clear cell renal cell carcinoma: a bioinformatic analysis.

Maelstrom (MAEL), a novel cancer/testis-associated gene, may facilitate the initiation and progression of human malignancies, warranting comprehensive investigations. Single-cell and tissue-bulk transcriptomic data demonstrated higher MAEL expression in testis (spermatogonia/spermatocyte), kidney (proximal tubular cell), and brain (neuron/astrocyte), and corresponding cancers, including testicular germ cell tumor, glioma, papillary renal cell carcinoma, and clear cell renal cell carcinoma (ccRCC). Of these cancers, only in ccRCC did MAEL expression exhibit associations with both recurrence-free survival and overall survival. High MAEL expression was associated with an anti-inflammatory tumor immune microenvironment and VEGFR/mTOR activation in ccRCC tissues and high sensitivities to VEGFR/PI3K-AKT-mTOR inhibitors in ccRCC cell lines. Consistent with these, low rather than high MAEL expression indicated remarkable progression-free survival benefits from immune checkpoint inhibitor (ICI)-based immunotherapies over VEGFR/mTOR inhibitors in two large phase III trials (JAVELIN Renal 101 and CheckMate-025). MAEL is a biologically and clinically significant determinant with potential for prognostication after nephrectomy and patient selection for VEGFR/mTOR inhibitors and immunotherapy-based treatments.

Spatiotemporal distribution, source apportionment, and ecological risk of bisphenol analogues in a highly urbanized river basin.

Bisphenol analogues (BPs), as one of the endocrine disruptors, have received wide attention due to their adverse impacts on ecosystems. However, the seasonal spatiotemporal distribution, source apportionment, and ecological risk of BPs in natural basins are poorly understood. Especially in highly urbanized river basins with the extensive economic development and anthropogenic activities threaten these critical but ecologically fragile regions. In this study, field investigations of BPs in the waters of the entire Qinhuai River Basin (QRB) were conducted in June (before the annual flood period) and August (after the annual flood period) 2023. The Qinhuai River, an important primary tributary of the lower Yangtze River, is located in eastern China and the QRB is characterized by a high population density and dense urbanization. Thirty-two sites were sampled for six types of BPs known to be ubiquitous in the surface water of the QRB. Significant differences in the concentrations of those BPs were found. Specifically, the concentration of total BPs (ΣBPs) was significantly higher before than after the flood period: 20.3-472 ng/L (mean = 146 ng/L) and 14.1-105 ng/L (mean = 35.9 ng/L), respectively. BPA was the main contributor to ΣBPs before the flood, and BPB followed by BPA after the flood. ΣBP concentrations were 12-241 % higher downstream than upstream of wastewater treatment plants (WWTPs). The results of a principal component analysis followed by multiple linear regression (PCA-MLR) suggested that untreated wastewater discharge from the WWTPs is an important source of BPs in the basin, with urban rainfall runoff as another potential source after the flood period. An assessment of the ecological risk of BPs, based on a calculation of the risk quotient, showed that BPA and BPS should be given due attention, and overall ecological risk of BPs pose a low risk to local algae but high and medium risks to invertebrates and fish, respectively.