FAT10 mediates the sorafenib-resistance of hepatocellular carcinoma cells by stabilizing E3 ligase NEDD4 to enhance PTEN/AKT pathway-induced autophagy.

Although sorafenib is the first-line therapeutic agent for advanced hepatocellular carcinoma (HCC), the development of drug resistance in HCC cells limits its clinical efficacy. However, the key factors involved in mediating the sorafenib resistance of HCC cells and the underlying mechanisms have not been elucidated. In this study, we generated sorafenib-resistant HCC cell lines, and our data demonstrate that HLA-F locus-adjacent transcript 10 (FAT10), a ubiquitin-like protein, is markedly upregulated in sorafenib-resistant HCC cells and that reducing the expression of FAT10 in sorafenib-resistant HCC cells increases sensitivity to sorafenib. Mechanistically, FAT10 stabilizes the expression of the PTEN-specific E3 ubiquitin ligase NEDD4 that causes downregulation of PTEN, thereby inducing AKT-mediated autophagy and promoting the resistance of HCC cells to sorafenib. Moreover, we screened the small molecule Compound 7695-0983, which increases the sensitivity of sorafenib-resistant HCC cells to sorafenib by inhibiting the expression of FAT10 to inhibit NEDD4-PTEN/AKT axis-mediated autophagy. Collectively, our preclinical findings identify FAT10 as a key factor in the sorafenib resistance of HCC cells and elucidate its underlying mechanism. This study provides new mechanistic insight for the exploitation of novel sorafenib-based tyrosine kinase inhibitor (TKI)-targeted drugs for treating advanced HCC.

Fused in sarcoma (FUS) inhibits milk production efficiency in mammals.

Efficient milk production in mammals confers evolutionary advantages by facilitating the transmission of energy from mother to offspring. However, the regulatory mechanism responsible for the gradual establishment of milk production efficiency in mammals, from marsupials to eutherians, remains elusive. Here, we find that mammary gland of the marsupial sugar glider contained milk components during adolescence, and that mammary gland development is less dynamically cyclic compared to that in placental mammals. Furthermore, fused in sarcoma (FUS) is found to be partially responsible for this establishment of low efficiency. In mouse model, FUS inhibit mammary epithelial cell differentiation through the cyclin-dependent kinase inhibitor p57Kip2, leading to lactation failure and pup starvation. Clinically, FUS levels are negatively correlated with milk production in lactating women. Overall, our results shed light on FUS as a negative regulator of milk production, providing a potential mechanism for the establishment of milk production from marsupial to eutherian mammals.

Changing trends in the disease burden of uterine cancer globally from 1990 to 2019 and its predicted level in 25 years.

Background: We aim to evaluate the global, regional, and national burden of Uterine Cancer (UC) from 1990 to 2019. Methods: We gathered UC data across 204 countries and regions for the period 1990-2019, utilizing the Global Burden of Disease Database (GBD) 2019 public dataset. Joinpoint regression analysis was employed to pinpoint the year of the most significant changes in global trends. To project the UC trajectory from 2020 to 2044, we applied the Nordpred analysis, extrapolating based on the average trend observed in the data. Furthermore, the Bayesian Age-Period-Cohort (BAPC) model with integrated nested Laplace approximations was implemented to confirm the stability of the Nordpred analysis predictions. Results: Globally, the age-standardized rate (ASR) of incidence for UC has increased from 1990 to 2019 with an Average Annual Percentage Change (AAPC) of 0.50%. The ASR for death has declined within the same period (AAPC: -0.8%). An increase in the ASR of incidence was observed across all Socio-demographic Index (SDI) regions, particularly in High SDI regions (AAPC: 1.12%), while the ASR for death decreased in all but the Low SDI regions. Over the past 30 years, the highest incidence rate was observed in individuals aged 55-59 (AAPC: 0.76%). Among 204 countries and regions, there was an increase in the ASR of incidence in 165 countries and an increase in the ASR of deaths in 77 countries. Our projections suggest that both the incidence and death rates for UC are likely to continue their decline from 2020 to 2044. Conclusions: UC has significantly impacted global health negatively, with its influence stemming from a range of factors including geographical location, age-related and racial disparities, and SDI.

[Simultaneous detection of lower aliphatic amines and conventional cations in atmospheric PM2.5 particulates by ion chromatography].

Many amine pollutants exist in the atmosphere. Lower aliphatic amines promote the formation and growth of particles into PM2.5, which damages the heart, lungs, and kidneys of the human body. PM2.5, a common atmospheric particulate pollutant with complex compositions, is the main cause of haze weather. Therefore, measuring the contents of lower aliphatic amines and cations in PM2.5 is of great significance for monitoring environmental air quality and protecting human health. This study established a suppressed ion-chromatographic method with conductivity for the simultaneous detection of four lower aliphatic amines (methylamine, dimethylamine, trimethylamine, and ethylamine) and five cations (Na+, N[Formula: see text], and Ca2+ showed high concentrations. The contents of the four lower aliphatic amines were low; however, the ethylamine content in some samples was high. The results indicate that the proposed method meets the quantification requirements for cations and lower aliphatic amines in PM2.5, with simple processing, high sensitivity, and good accuracy. It can quickly and accurately detect a large number of samples and be used to assess the pollution of small particles in the air as well as trace pollution sources to protect human health.

Functional analysis of the mating type genes in Verticillium dahliae.

BACKGROUND: Populations of the plant pathogenic fungus Verticillium dahliae display a complex and rich genetic diversity, yet the existence of sexual reproduction in the fungus remains contested. As pivotal genes, MAT genes play a crucial role in regulating cell differentiation, morphological development, and mating of compatible cells. However, the functions of the two mating type genes in V. dahliae, VdMAT1-1-1, and VdMAT1-2-1, remain poorly understood. RESULTS: In this study, we confirmed that the MAT loci in V. dahliae are highly conserved, including both VdMAT1-1-1 and VdMAT1-2-1 which share high collinearity. The conserved core transcription factor encoded by the two MAT loci may facilitate the regulation of pheromone precursor and pheromone receptor genes by directly binding to their promoter regions. Additionally, peptide activity assays demonstrated that the signal peptide of the pheromone VdPpg1 possessed secretory activity, while VdPpg2, lacked a predicted signal peptide. Chemotactic growth assays revealed that V. dahliae senses and grows towards the pheromones FO-a and FO-α of Fusarium oxysporum, as well as towards VdPpg2 of V. dahliae, but not in response to VdPpg1. The findings herein also revealed that VdMAT1-1-1 and VdMAT1-2-1 regulate vegetative growth, carbon source utilization, and resistance to stressors in V. dahliae, while negatively regulating virulence. CONCLUSIONS: These findings underscore the potential roles of VdMAT1-1-1 and VdMAT1-2-1 in sexual reproduction and confirm their involvement in various asexual processes of V. dahliae, offering novel insights into the functions of mating type genes in this species.

A Lightweight and Affordable Wearable Haptic Controller for Robot-Assisted Microsurgery.

In robot-assisted microsurgery (RAMS), surgeons often face the challenge of operating with minimal feedback, particularly lacking in haptic feedback. However, most traditional desktop haptic devices have restricted operational areas and limited dexterity. This report describes a novel, lightweight, and low-budget wearable haptic controller for teleoperated microsurgical robotic systems. We designed a wearable haptic interface entirely made using off-the-shelf material-PolyJet Photopolymer, fabricated using liquid and solid hybrid 3D co-printing technology. This interface was designed to resemble human soft tissues and can be wrapped around the fingertips, offering direct contact feedback to the operator. We also demonstrated that the device can be easily integrated with our motion tracking system for remote microsurgery. Two motion tracking methods, marker-based and marker-less, were compared in trajectory-tracking experiments at different depths to find the most effective motion tracking method for our RAMS system. The results indicate that within the 4 to 8 cm tracking range, the marker-based method achieved exceptional detection rates. Furthermore, the performance of three fusion algorithms was compared to establish the unscented Kalman filter as the most accurate and reliable. The effectiveness of the wearable haptic controller was evaluated through user studies focusing on the usefulness of haptic feedback. The results revealed that haptic feedback significantly enhances depth perception for operators during teleoperated RAMS.

Microbial-mediated conversion of soil organic carbon co-regulates the evolution of antibiotic resistance.

The influence of organic carbon on the proliferation of antibiotic resistance genes (ARGs) in the soil has been widely documented. However, it is unclear how soil organic carbon (SOC) interacts with the evolution of antibiotic resistance in bacteria. Here, we examined the variations in ARGs abundance during SOC mineralization and explored the microbiological mechanisms and key metabolic pathways involved in their coevolution. The results showed that the SOC mineralization rate was closely correlated with ARGs abundance (p < 0.05). High organic carbon (OC) mineralization was conducive to the occurrence of multidrug resistance genes. For example, multidrug_transporter and mexB increased 2.26 and 7.83 times from the initial level. The competitor (stress) evolutionary strategy model revealed that higher OC inputs drive environmental microorganisms to evolve from stress tolerant to high resistance and strong adaptation. Meta-genomic and transcriptomic analyses revealed that the conversion process of pyruvate to acetyl-CoA to acetate was the critical metabolic pathway for the co-regulation of antibiotic resistance. Gene deletion validation trials have demonstrated that the key functional genes (ackA and pta) involved in this process can modulate the development of vancomycin and multidrug resistance. This outcome provides a preliminary framework for microbial mechanisms that target the co-regulation of microbial OC conversion and the evolution of antibiotic resistance.

Brain stimulation over the left DLPFC enhances motivation for effortful rewards in patients with major depressive disorder.

BACKGROUND: Amotivation is a typical feature in major depressive disorder (MDD), which produces reduced willingness to exert effort. The dorsolateral prefrontal cortex (DLPFC) is a crucial structure in goal-directed actions and therefore is a potential target in modulating effortful motivation. However, it remains unclear whether the intervention is effective for patients with MDD. METHODS: We employed transcranial magnetic stimulation (TMS), computational modelling and event-related potentials (ERPs) to reveal the causal relationship between the left DLPFC and motivation for effortful rewards in MDD. Fifty patients underwent both active and sham TMS sessions, each followed by performing an Effort-Expenditure for Rewards Task, during which participants chose and implemented between low-effort/low-reward and high-effort/high-reward options. RESULTS: The patients showed increased willingness to exert effort for rewards during the DLPFC facilitated session, compared with the sham session. They also had a trend in larger P3 amplitude for motivated attention toward chosen options, larger CNV during preparing for effort exertion, and larger SPN during anticipating a high reward. Besides, while behavior indexes for effortful choices were negatively related to depression severity in the sham session, this correlation was weakened in the active stimulation session. CONCLUSIONS: These findings provide behavioral, computational, and neural evidence for the left DLPFC on effortful motivation for rewards. Facilitated DLPFC improves motor preparation and value anticipation after making decisions especially for highly effortful rewards in MDD. Facilitated DLPFC also has a potential function in enhancing motivated attention during cost-benefit trade-off. This neuromodulation effect provides a potential treatment for improving motivation in clinics.

Proteomic characteristics of the aqueous humor in Uyghur patients with pseudoexfoliation syndrome and pseudoexfoliative glaucoma.

Pseudoexfoliation syndrome (PEX) is characterized by the deposition of fibrous pseudoexfoliation material (PEXM) in the eye, and secondary glaucoma associated with this syndrome has a faster and more severe clinical course. The incidence of PEX and pseudoexfoliative glaucoma (PEXG) exhibits ethnic clustering; however, few proteomic studies related to PEX and PEXG have been conducted in Asian populations. Therefore, we aimed to conduct proteomic analysis on the aqueous humor (AH) obtained from Uyghur patients with cataracts, those with PEX and cataracts, and those with PEXG and cataracts to better understand the molecular mechanisms of the disease and identify its potential biomarkers. To this end, AH was collected from patients with cataracts (n = 10, control group), PEX with cataracts (n = 10, PEX group), and PEXG with cataracts (n = 10, PEXG group) during phacoemulsification. Label-free quantitative proteomic techniques combined with bioinformatics were used to identify and analyze differentially expressed proteins (DEPs) in the AH of PEX and PEXG groups. Then, independent AH samples (n = 12, each group) were collected to validate DEPs by enzyme-linked immunosorbent assay (ELISA). The PEX group exhibited 25 DEPs, while the PEXG group showed 44 DEPs, both compared to the control group. Subsequently, we found three newly identified proteins in both PEX and PEXG groups, wherein FRAS1-related extracellular matrix protein 2 (FREM2) and osteoclast-associated receptor (OSCAR) exhibited downregulation, whereas coagulation Factor IX (F9) displayed upregulation. Bioinformatics analysis suggested that extracellular matrix interactions, abnormal blood-derived proteins, and lysosomes were mainly involved in the process of PEX and PEXG, and the PPI network further revealed F9 may serve as a potential biomarker for both PEX and PEXG. In conclusion, this study provides new information for understanding the proteomics of AH in PEX and PEXG.

Detection of iodixanol-induced allergic reaction signals in Chinese inpatients: a multi-center retrospective database study using prescription sequence symmetry analysis.

Objective: This study aimed to explore the signal detection method for allergic reactions induced by inpatient iodixanol injection. Methods: A database of 3,719,217 hospitalized patients from 20 large Chinese general hospitals was processed and analyzed using the prescription sequence symmetry analysis (PSSA) method. Results: 126,680 inpatients who used iodixanol and were concurrently treated with anti-allergic drugs were analyzed. In the medical records of these patients, only 32 had documented iodixanol allergies. Statistical analysis identified 22 drugs in 4 categories-calcium preparations, adrenergic/dopaminergic agents, glucocorticoids, and antihistamines-as marker drugs. With time intervals of 3, 7, and 28 days, the adjusted sequence ratios (aSRs) for all anti-allergics and the 4 categories were greater than 1. The 7-day aSRs were 2.12 (95% CI: 2.08-2.15), 1.70 (95% CI: 1.68-1.73), 3.85 (95% confidence interval [CI]: 3.75-2.30), 2.30 (95% CI: 2.26-2.35), and 1.95 (95% CI: 1.89-2.02), respectively. The proportions of adverse drug events indicated by each signal were as follows: all anti-allergics (2.92%-3%), calcium gluconate (0.19%-0.52%), adrenergic/dopaminergic agents (2.20%-3.37%), glucocorticoids (3.13%-3.76%), and antihistamines (1.05%-1.32%). Conclusion: This first multi-center Chinese inpatient database study detected iodixanol-induced allergy signals, revealing that reactions may be much higher than those in collected spontaneous reports. Iodixanol risk exposure was closer to actual pharmaceutical care findings. PSSA application with ≤7-day intervals appears better suited for monitoring late allergic reaction signals with these drugs.

Probiotics for the prevention of gestational diabetes mellitus: A meta-analysis of randomized controlled trials.

Changes of intestinal microbiota have been shown to be involved in the development of gestational diabetes mellitus (GDM). We performed a meta-analysis to systematically evaluate the potential role of probiotics for the prevention of GDM. Systematic literature search was performed in electronic databases including PubMed, Cochrane library, Embase, Web of Science, Wanfang, and China National Knowledge Infrastructure (CNKI) to obtain relevant randomized controlled studies. A random-effects model was used to pool the results by incorporating the impact of the potential heterogeneity. Meta-regression and subgroup analyses were conducted to evaluate the source of heterogeneity. Fourteen studies involving 3527 pregnant women were included. Results showed that probiotics significantly reduced the incidence of GDM as compared to control (risk ratio [RR]: 0.71, 95% confidence interval [CI]: 0.52-0.96, P = 0.03) with significant heterogeneity (I2 = 73%). The meta-regression showed that body mass index (BMI) of females was positively associated with the RR for the effect of probiotics on GDM (coefficient = 0.084, P = 0.01). The results of subgroup analyses also suggested that probiotics significantly reduced the risk of GDM in women with BMI < 26 kg/m2, but not in those with BMI ≥ 26 kg/m2 (P for subgroup difference = 0.001). In addition, the preventative efficacy of probiotics on GDM was remarkable in women < 30 years, but not in those ≥ 30 years (P for subgroup difference < 0.001). In conclusion, probiotics may be effective in reducing the risk of GDM, particularly for females with lower BMI and younger age.

A new model construction based on the knowledge graph for mining elite polyphenotype genes in crops.

Identifying polyphenotype genes that simultaneously regulate important agronomic traits (e.g., plant height, yield, and disease resistance) is critical for developing novel high-quality crop varieties. Predicting the associations between genes and traits requires the organization and analysis of multi-dimensional scientific data. The existing methods for establishing the relationships between genomic data and phenotypic data can only elucidate the associations between genes and individual traits. However, there are relatively few methods for detecting elite polyphenotype genes. In this study, a knowledge graph for traits regulating-genes was constructed by collecting data from the PubMed database and eight other databases related to the staple food crops rice, maize, and wheat as well as the model plant Arabidopsis thaliana. On the basis of the knowledge graph, a model for predicting traits regulating-genes was constructed by combining the data attributes of the gene nodes and the topological relationship attributes of the gene nodes. Additionally, a scoring method for predicting the genes regulating specific traits was developed to screen for elite polyphenotype genes. A total of 125,591 nodes and 547,224 semantic relationships were included in the knowledge graph. The accuracy of the knowledge graph-based model for predicting traits regulating-genes was 0.89, the precision rate was 0.91, the recall rate was 0.96, and the F1 value was 0.94. Moreover, 4,447 polyphenotype genes for 31 trait combinations were identified, among which the rice polyphenotype gene IPA1 and the A. thaliana polyphenotype gene CUC2 were verified via a literature search. Furthermore, the wheat gene TraesCS5A02G275900 was revealed as a potential polyphenotype gene that will need to be further characterized. Meanwhile, the result of venn diagram analysis between the polyphenotype gene datasets (consists of genes that are predicted by our model) and the transcriptome gene datasets (consists of genes that were differential expression in response to disease, drought or salt) showed approximately 70% and 54% polyphenotype genes were identified in the transcriptome datasets of Arabidopsis and rice, respectively. The application of the model driven by knowledge graph for predicting traits regulating-genes represents a novel method for detecting elite polyphenotype genes.

Nitrogen and sulfur cycling and their coupling mechanisms in eutrophic lake sediment microbiomes.

Microorganisms play important roles in the biogeochemical cycles of lake sediment. However, the integrated metabolic mechanisms governing nitrogen (N) and sulfur (S) cycling in eutrophic lakes remain poorly understood. Here, metagenomic analysis of field and bioreactor enriched sediment samples from a typical eutrophic lake were applied to elucidate the metabolic coupling of N and S cycling. Our results showed significant diverse genes involved in the pathways of dissimilatory sulfur metabolism, denitrification and dissimilatory nitrate reduction to ammonium (DNRA). The N and S associated functional genes and microbial groups generally showed significant correlation with the concentrations of NH4+, NO2- and SO42, while with relatively low effects from other environmental factors. The gene-based co-occurrence network indicated clear cooperative interactions between N and S cycling in the sediment. Additionally, our analysis identified key metabolic processes, including the coupled dissimilatory sulfur oxidation (DSO) and DNRA as well as the association of thiosulfate oxidation complex (SOX systems) with denitrification pathway. However, the enriched N removal microorganisms in the bioreactor ecosystem demonstrated an additional electron donor, incorporating both the SOX systems and DSO processes. Metagenome-assembled genomes-based ecological model indicated that carbohydrate metabolism is the key linking factor for the coupling of N and S cycling. Our findings uncover the coupling mechanisms of microbial N and S metabolism, involving both inorganic and organic respiration pathways in lake sediment. This study will enhance our understanding of coupled biogeochemical cycles in lake ecosystems.

Recent advances in nucleic acid signal amplification-based aptasensors for sensing mycotoxins.

Mycotoxin contamination in food products may cause serious health hazards and economic losses. The effective control and accurate detection of mycotoxins have become a global concern. Even though a variety of methods have been developed for mycotoxin detection, most conventional methods suffer from complicated operation procedures, low sensitivity, high cost, and long assay time. Therefore, the development of simple and sensitive methods for mycotoxin assay is highly needed. The introduction of nucleic acid signal amplification technology (NASAT) into aptasensors significantly improves the sensitivity and facilitates the detection of mycotoxins. Herein, we give a comprehensive review of the recent advances in NASAT-based aptasensors for assaying mycotoxins and summarize the principles, features, and applications of NASAT-based aptasensors. Moreover, we highlight the challenges and prospects in the field, including the simultaneous detection of multiple mycotoxins and the development of portable devices for field detection.

Characterization of the complete chloroplast genome sequence of Camellia tetracocca (Theaceae).

Camellia tetracocca H.T. Chang 1981 is an important wild relative of cultivated tea plants. Its leaves are widely used by local people to make tea, showing great economic and breeding values. We here report the complete chloroplast genome of C. tetracocca using Illumina sequencing technology. The complete chloroplast genome of C. tetracocca is 157,026 bp in length, and structurally contains a pair of inverted repeat regions (IRa and IRb, 26,052 bp) separated by a large single-copy region (LSC, 86,669 bp) and a small single-copy region (SSC, 18,253 bp). It is composed of 131 predicted genes, including 86 protein-coding genes, 37 transfer RNA genes, and eight ribosomal RNA genes. The overall GC content is 37.31%. Phylogenetic analysis among four Camellia species and 11 other close species reveals a close relationship between C. tetracocca and C. gymnogyna.

Enhancing ventrolateral prefrontal cortex activation mitigates social pain and modifies subsequent social attitudes: Insights from TMS and fMRI.

Social pain, a multifaceted emotional response triggered by interpersonal rejection or criticism, profoundly impacts mental well-being and social interactions. While prior research has implicated the right ventrolateral prefrontal cortex (rVLPFC) in mitigating social pain, the precise neural mechanisms and downstream effects on subsequent social attitudes remain elusive. This study employed transcranial magnetic stimulation (TMS) integrated with fMRI recordings during a social pain task to elucidate these aspects. Eighty participants underwent either active TMS targeting the rVLPFC (n = 41) or control stimulation at the vertex (n = 39). Our results revealed that TMS-induced rVLPFC facilitation significantly reduced self-reported social pain, confirming the causal role of the rVLPFC in social pain relief. Functional connectivity analyses demonstrated enhanced interactions between the rVLPFC and the dorsolateral prefrontal cortex, emphasizing the collaborative engagement of prefrontal regions in emotion regulation. Significantly, we observed that negative social feedback led to negative social attitudes, whereas rVLPFC activation countered this detrimental effect, showcasing the potential of the rVLPFC as a protective buffer against adverse social interactions. Moreover, our study uncovered the impact role of the hippocampus in subsequent social attitudes, a relationship particularly pronounced during excitatory TMS over the rVLPFC. These findings offer promising avenues for improving mental health within the intricate dynamics of social interactions. By advancing our comprehension of the neural mechanisms underlying social pain relief, this research introduces novel intervention strategies for individuals grappling with social distress. Empowering individuals to modulate rVLPFC activation may facilitate reshaping social attitudes and successful reintegration into communal life.

Genetic dissection and identification of stripe rust resistance genes in the wheat cultivar Lanhangxuan 121, a cultivar selected from a space mutation population.

Stripe rust is a devastating disease of wheat worldwide. Chinese wheat cultivar Lanhangxuan 121 (LHX121), selected from an advanced line L92-47 population that had been subjected to space mutation breeding displayed a consistently higher level of resistance to stipe rust than its parent in multiple field environments. The aim of this research was to establish the number and types of resistance genes in parental lines L92-47 and LHX121 using separate segregating populations. The first population developed from a cross between LHX121 and susceptible cultivar Xinong 822 comprised 278 F2:3 lines. The second validation population comprised 301 F2:3 lines from a cross between L92-47 and susceptible cultivar Xinong 979. Lines of two population were evaluated for stripe rust response at three sites during the 2018-2020 cropping season. Affymetrix 660 K SNP arrays were used to genotype the lines and parents. Inclusive composite interval mapping detected QTL QYrLHX.nwafu-2BS, QYrLHX.nwafu-3BS, and QYrLHX.nwafu-5BS for resistance in all three environments. Based on previous studies and pedigree information, QYrLHX.nwafu-2BS and QYrLHX.nwafu-3BS were likely to be Yr27 and Yr30 that are present in the L92-47 parent. QYrLHX.nwafu-5BS (YrL121) detected only in LHX121 was mapped to a 7.60 cM interval and explained 10.67-22.57% of the phenotypic variation. Compared to stripe rust resistance genes previously mapped to chromosome 5B, YrL121 might be a new adult plant resistance QTL. Furthermore, there were a number of variations signals using 35 K SNP array and differentially expressed genes using RNA-seq between L92-47 and LHX121 in the YrL121 region, indicating that they probably impair the presence and/or function of YrL121. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-024-01461-0.

Deep learning on tertiary lymphoid structures in hematoxylin-eosin predicts cancer prognosis and immunotherapy response.

Tertiary lymphoid structures (TLSs) have been associated with favorable immunotherapy responses and prognosis in various cancers. Despite their significance, their quantification using multiplex immunohistochemistry (mIHC) staining of T and B lymphocytes remains labor-intensive, limiting its clinical utility. To address this challenge, we curated a dataset from matched mIHC and H&E whole-slide images (WSIs) and developed a deep learning model for automated segmentation of TLSs. The model achieved Dice coefficients of 0.91 on the internal test set and 0.866 on the external validation set, along with intersection over union (IoU) scores of 0.819 and 0.787, respectively. The TLS ratio, defined as the segmented TLS area over the total tissue area, correlated with B lymphocyte levels and the expression of CXCL13, a chemokine associated with TLS formation, in 6140 patients spanning 16 tumor types from The Cancer Genome Atlas (TCGA). The prognostic models for overall survival indicated that the inclusion of the TLS ratio with TNM staging significantly enhanced the models' discriminative ability, outperforming the traditional models that solely incorporated TNM staging, in 10 out of 15 TCGA tumor types. Furthermore, when applied to biopsied treatment-naïve tumor samples, higher TLS ratios predicted a positive immunotherapy response across multiple cohorts, including specific therapies for esophageal squamous cell carcinoma, non-small cell lung cancer, and stomach adenocarcinoma. In conclusion, our deep learning-based approach offers an automated and reproducible method for TLS segmentation and quantification, highlighting its potential in predicting immunotherapy response and informing cancer prognosis.

Amyloid pathology mediates the associations between plasma fibrinogen and cognition in non-demented adults.

Though previous studies revealed the potential associations of elevated levels of plasma fibrinogen with dementia, there is still limited understanding regarding the influence of Alzheimer's disease (AD) biomarkers on these associations. We sought to investigate the interrelationships among fibrinogen, cerebrospinal fluid (CSF) AD biomarkers, and cognition in non-demented adults. We included 1996 non-demented adults from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study and 337 from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The associations of fibrinogen with AD biomarkers and cognition were explored using multiple linear regression models. The mediation analyses with 10 000 bootstrapped iterations were conducted to explore the mediating effects of AD biomarkers on cognition. In addition, interaction analyses and subgroup analyses were conducted to assess the influence of covariates on the relationships between fibrinogen and AD biomarkers. Participants exhibiting low Aß42 were designated as A+, while those demonstrating high phosphorylated tau (P-tau) and total tau (Tau) were labeled as T+ and N+, respectively. Individuals with normal measures of Aß42 and P-tau were categorized as the A-T- group, and those with abnormal levels of both Aß42 and P-tau were grouped under A+T+. Fibrinogen was higher in the A+ subgroup compared to that in the A- subgroup (p = 0.026). Fibrinogen was higher in the A+T+ subgroup compared to that in the A-T- subgroup (p = 0.011). Higher fibrinogen was associated with worse cognition and Aß pathology (all p < 0.05). Additionally, the associations between fibrinogen and cognition were partially mediated by Aß pathology (mediation proportion range 8%-28%). Interaction analyses and subgroup analyses showed that age and ApoE ε4 affect the relationships between fibrinogen and Aß pathology. Fibrinogen was associated with both cognition and Aß pathology. Aß pathology may be a critical mediator for impacts of fibrinogen on cognition.