Mutational signature and prognosis in adenocarcinoma of the bladder.

Adenocarcinoma of the bladder is a rare urinary bladder carcinoma with limited therapy options due to lack of molecular characterization. Here, we aimed to reveal the mutational and transcriptomic landscapes of adenocarcinoma of the bladder and assess any relationship with prognosis. Between February 2015 and June 2021, a total of 23 patients with adenocarcinoma of the bladder were enrolled. These included 16 patients with primary bladder adenocarcinomas and seven patients with urachal adenocarcinoma. Whole exome sequencing (16 patients), whole genome sequencing (16 patients), bulk RNA sequencing (RNA-seq) (19 patients), and single-cell RNA-seq (5 patients) were conducted for the specimens. Correlation analysis, survival analysis, and t-tests were also performed. Prevalent T>A substitutions were observed among somatic mutations, and major trinucleotide contexts included 5'-CTC-3' and 5'-CTG-3'. This pattern was mainly contributed by COSMIC signature 22 related to chemical carcinogen exposure (probably aristolochic acid), which has not been reported in bladder adenocarcinoma. Moreover, genes with copy number changes were also enriched in the KEGG term 'chemical carcinogenesis'. Transcriptomic analysis suggested high immune cell infiltration and luminal-like features in the majority of samples. Interestingly, a small fraction of samples with an APOBEC-derived mutational signature exhibited a higher risk of disease progression compared with samples with only a chemical carcinogen-related signature, confirming the molecular and prognostic heterogeneity of bladder adenocarcinoma. This study presents mutational and transcriptomic landscapes of bladder adenocarcinoma, and indicates that a chemical carcinogen-related mutational signature may be related to a better prognosis compared with an APOBEC signature in adenocarcinoma of the bladder. © 2024 The Pathological Society of Great Britain and Ireland.

Factor of DNA methylation 1 affects woodland strawberry plant stature and organ size via DNA methylation.

RNA-directed DNA methylation (RdDM) is an epigenetic process that directs silencing to specific genomic regions and loci. The biological functions of RdDM are not well studied in horticultural plants. Here, we isolated the ethyl methane-sulfonate-induced mutant reduced organ size (ros) producing small leaves, flowers, and fruits in woodland strawberry (Fragaria vesca) due to reduced cell numbers compared with that in the wild-type (WT). The candidate mutation causes a premature stop codon in FvH4_6g28780, which shares high similarity to Arabidopsis (Arabidopsis thaliana) Factor of DNA Methylation1 (FDM1) encoding an RdDM pathway component and was named FveFDM1. Consistently, the fvefdm1CR mutants generated by CRISPR/Cas9 also produced smaller organs. Overexpressing FveFDM1 in an Arabidopsis fdm1-1 fdm2-1 double mutant restored DNA methylation at the RdDM target loci. FveFDM1 acts in a protein complex with its homolog Involved in De Novo 2 (FveIDN2). Furthermore, whole-genome bisulfite sequencing revealed that DNA methylation, especially in the CHH context, was remarkably reduced throughout the genome in fvefdm1. Common and specific differentially expressed genes were identified in different tissues of fvefdm1 compared to in WT tissues. DNA methylation and expression levels of several gibberellic acid (GA) biosynthesis and cell cycle genes were validated. Moreover, the contents of GA and auxin were substantially reduced in the young leaves of fvefdm1 compared to in the WT. However, exogenous application of GA and auxin could not recover the organ size of fvefdm1. In addition, expression levels of FveFDM1, FveIDN2, Nuclear RNA Polymerase D1 (FveNRPD1), Domains Rearranged Methylase 2 (FveDRM2), and cell cycle genes were greatly induced by GA treatment. Overall, our work demonstrated the critical roles of FveFDM1 in plant growth and development via RdDM-mediated DNA methylation in horticultural crops.

Effects of Three Kinds of Carbohydrate Pharmaceutical Excipients-Fructose, Lactose and Arabic Gum on Intestinal Absorption of Gastrodin through Glucose Transport Pathway in Rats.

BACKGROUND: Some glucoside drugs can be transported via intestinal glucose transporters (IGTs), and the presence of carbohydrate excipients in pharmaceutical formulations may influence the absorption of them. This study, using gastrodin as probe drug, aimed to explore the effects of fructose, lactose, and arabic gum on intestinal drug absorption mediated by the glucose transport pathway. METHODS: The influence of fructose, lactose, and arabic gum on gastrodin absorption was assessed via pharmacokinetic experiments and single-pass intestinal perfusion. The expression of sodium-dependent glucose transporter 1 (SGLT1) and sodium-independent glucose transporter 2 (GLUT2) was quantified via RT‒qPCR and western blotting. Alterations in rat intestinal permeability were evaluated through H&E staining, RT‒qPCR, and immunohistochemistry. RESULTS: Fructose reduced the area under the curve (AUC) and peak concentration (Cmax) of gastrodin by 42.7% and 63.71%, respectively (P < 0.05), and decreased the effective permeability coefficient (Peff) in the duodenum and jejunum by 58.1% and 49.2%, respectively (P < 0.05). SGLT1 and GLUT2 expression and intestinal permeability remained unchanged. Lactose enhanced the AUC and Cmax of gastrodin by 31.5% and 65.8%, respectively (P < 0.05), and increased the Peff in the duodenum and jejunum by 33.7% and 26.1%, respectively (P < 0.05). SGLT1 and GLUT2 levels did not significantly differ, intestinal permeability increased. Arabic gum had no notable effect on pharmacokinetic parameters, SGLT1 or GLUT2 expression, or intestinal permeability. CONCLUSION: Fructose, lactose, and arabic gum differentially affect intestinal drug absorption through the glucose transport pathway. Fructose competitively inhibited drug absorption, while lactose may enhance absorption by increasing intestinal permeability. Arabic gum had no significant influence.

One stone two birds - Submucosal tunneling endoscopic resection for a large esophageal submucosal mass and esophageal diverticulum.

A-35-year-old woman presented our hospital with half a year's history of solid food dysphagia. An upper gastrointestinal endoscopy revealed a large submucosal mass in an esophageal diverticulum near the gastroesophageal junction. Endoscopic ultrasound (EUS) confirmed a hypoechoic lesion arising from the muscularis propria layer with the size of 25*14 mm. Therefore, submucosal tunneling endoscopic resection (STER) was proposed to remove the large submucosal lesion in addition to targeted septotomy of the esophageal diverticula. A 2-cm longitudinal mucosal access was made at 3 cm above the submucosal lesion, and a submucosal longitudinal tunnel was created until the submucosal lesion revealed using a DualKnife (Olympus, Japan). Meticulous resection was performed with the DualKnife, and the lateral border of the lesion was dissected from muscularis propria layer. It was completely removed the lesion with en bolc resection, and dissected the septum of the diverticulum using the DualKnife. The tunnel access was closed with several hemoclips. Finally, it has been demonstrated to achieve a perfect outcome for the patient. The patient was discharged three days later with symptom resolved on follow-up and to date.

Endoloop pre-ligation assisted resection of a giant Brunner's gland adenoma of the duodenal bulb.

Brunner's gland adenoma (BGA), also known as Brunneroma or polypoid hamartoma, is a rare benign duodenal tumor that proliferates from Brunner's glands of the duodenum. They are usually asymptomatic and discovered by chance during endoscopy. Some giant lesions can sometimes present with chronic abdominal pain, nausea, vomiting, and anemia, including gastrointestinal bleeding and obstructive symptoms, and need to be resected by surgery or endoscopy. Here we report a giant BGA that was easily and safely removed by Endoloop pre-ligation assisted resection.

Effects of Commonly used Surfactants, Poloxamer 188 and Tween 80, on the Drug Transport Capacity of Intestinal Glucose Transporters.

Some glycoside drugs can be transported through intestinal glucose transporters (IGTs). The surfactants used in oral drug preparations can affect the function of transporter proteins. This study aimed to investigate the effect of commonly used surfactants, Poloxamer 188 and Tween 80, on the drug transport capacity of IGTs. Previous studies have shown that gastrodin is the optimal drug substrate for IGTs. Gastrodin was used as a probe drug to evaluate the effect of these two surfactants on intestinal absorption in SD rats through pharmacokinetic and in situ single-pass intestinal perfusion. Then, the effects of the two surfactants on the expression of glucose transporters and tight-junction proteins were examined using RT-PCR and western blotting. Additionally, the effect of surfactants on intestinal permeability was evaluated through hematoxylin-eosin staining. The results found that all experimental for Poloxamer 188 (0.5%, 2.0% and 8.0%) and Tween 80 (0.1% and 2.0%) were not significantly different from those of the blank group. However, the AUC(0-∞) of gastrodin increased by approximately 32% when 0.5% Tween 80 was used. The changes in IGT expression correlated with the intestinal absorption of gastrodin. A significant increase in the expression of IGTs was observed at 0.5% Tween 80. In conclusion, Poloxamer 188 had minimal effect on the drug transport capacity of IGTs within the recommended limits of use. However, the expression of IGTs increased in response to 0.5% Tween 80, which significantly enhanced the drug transport capacity of IGTs. However, 0.1% and 2.0% Tween 80 had no significant effect.

Androgen receptor and MYC transcriptomes are equilibrated in multilayer regulatory circuitries in prostate cancer.

BACKGROUND: The discovery of androgen receptor (AR) having transrepression effects completes the circle of its functionalities as a typical transcription factor, which intrinsically bears dual functions of activation and repression linked to co-factor competition and redistribution. Indeed, AR dual functions are exemplified by locus-wide regulation of the oncogenic 8q24-MYC region. METHODS: RT-qPCR assay and public RNA-profiling datasets were used to assess MYC transcription in androgen-sensitive cell lines. Public ChIP-seq and RNA-Seq datasets were computed to evaluate AR-MYC direct and indirect signatures. Gene sets in typical MYC and AR pathways were monitored to validate their cross-talks. Bio-informatics and chromosome conformation capture (3C) assay were performed in the AR gene locus to examine androgen-elicited distal regulation. Finally, co-factor re-distribution were globally tracked between AR and MYC binding sites. RESULTS: In this report, we found MYC responded negatively to androgen with hypersensitivity, rivaling AR natural functions as an innate androgen effector. Furthermore, both direct and indirect AR and MYC transcriptional programs were actively in equilibration. With established androgen-mediated versus MYC-mediated gene subsets, we validated AR and MYC pathways were both bidirectional and extensively entangled. In addition, we determined that the AR gene locus resembled the MYC gene region and both loci were androgen-repressed via epigenetics and chromatin architectural alterations. Significantly, transcriptional factor profiling along the prostate cancer (PCa) genome exposed that PCa transcriptomes were dynamically equilibrated between AR-binding site and MYC-binding site. CONCLUSION: Together, our findings stratified AR-MYC interactions that are extensively wired and intricately organized to compensate for essential PCa transcriptional programs and neutralize excessive signaling.

Multimodal-based machine learning strategy for accurate and non-invasive prediction of intramedullary glioma grade and mutation status of molecular markers: a retrospective study.

BACKGROUND: Determining the grade and molecular marker status of intramedullary gliomas is important for assessing treatment outcomes and prognosis. Invasive biopsy for pathology usually carries a high risk of tissue damage, especially to the spinal cord, and there are currently no non-invasive strategies to identify the pathological type of intramedullary gliomas. Therefore, this study aimed to develop a non-invasive machine learning model to assist doctors in identifying the intramedullary glioma grade and mutation status of molecular markers. METHODS: A total of 461 patients from two institutions were included, and their sagittal (SAG) and transverse (TRA) T2-weighted magnetic resonance imaging scans and clinical data were acquired preoperatively. We employed a transformer-based deep learning model to automatically segment lesions in the SAG and TRA phases and extract their radiomics features. Different feature representations were fed into the proposed neural networks and compared with those of other mainstream models. RESULTS: The dice similarity coefficients of the Swin transformer in the SAG and TRA phases were 0.8697 and 0.8738, respectively. The results demonstrated that the best performance was obtained in our proposed neural networks based on multimodal fusion (SAG-TRA-clinical) features. In the external validation cohort, the areas under the receiver operating characteristic curve for graded (WHO I-II or WHO III-IV), alpha thalassemia/mental retardation syndrome X-linked (ATRX) status, and tumor protein p53 (P53) status prediction tasks were 0.8431, 0.7622, and 0.7954, respectively. CONCLUSIONS: This study reports a novel machine learning strategy that, for the first time, is based on multimodal features to predict the ATRX and P53 mutation status and grades of intramedullary gliomas. The generalized application of these models could non-invasively provide more tumor-specific pathological information for determining the treatment and prognosis of intramedullary gliomas.

Dissecting transcription of the 8q24-MYC locus in prostate cancer recognizes the equilibration between androgen receptor direct and indirect dual-functions.

BACKGROUND: Androgen receptor (AR) activation and repression dual-functionality only became known recently and still remains intriguing in prostate cancer (PCa). MYC is a prominent oncogene that functionally entangles with AR signaling in PCa. Further exploration of AR regulatory mechanisms on MYC gene transcription bears clinical and translation significance. METHODS: Bioinformatics analysis of PCa cell line and clinical RNA-Seq and ChIP-Seq (chromatin immunoprecipitation-sequencing) datasets to anchor interactions of AR and MYC transcriptional networks. ChIP-qPCR and 3C (chromosome conformation capture) analyses to probe MYC distal regulation by AR binding sites (ABSs). CRISPR/Cas9-mediated genome-editing to specify functions of ABS within the 8q24-MYC locus on androgen-mediated MYC transcription. Global FoxA1 and HoxB13 distribution profiling to advance AR transcriptional mechanisms. RESULTS: Here we recognize AR bi-directional transcription mechanisms by exploiting the prominent 8q24-MYC locus conferring androgen hyper-sensitivity. At ~ 25 Kb downstream of the MYC gene, we identified an undefined ABS, P10. By chromatin analyses, we validated androgen-dependent spatial interaction between P10 and MYC-Promoter (MYC-Pro) and temporal epigenetic repression of these MYC-proximal elements. We next designed a CRISPR/Cas9-mediated double genomic knock-out (KO) strategy to show that P10-KO slightly lessened androgen-elicited MYC transrepression in LNCaP-AR cells. In similar genomic editing assays, androgen-mediated MYC repression became slightly deepened upon KO of P11, an ABS in the PVT1 gene locus highly enriched in AR-binding motifs and peaks. We also investigated multiple ABSs in the established PCAT1 super-enhancer that distally interacts with MYC-Pro for transactivation, with each KO pool consistently shown to relieve androgen-elicited MYC repression. In the end, we systemically assessed androgen effects in the 8q24-MYC locus and along PCa genome to generalize H3K27ac and BRD4 re-distribution from pioneer factors (FoxA1 and HoxB13) to AR sites. CONCLUSION: Together, we reconciled these observations by unifying AR dual-functions that are mechanistically coupled to and equilibrated by co-factor redistribution.

Active quasi-BIC metasurfaces assisted by epsilon-near-zero materials.

Active devices play a critical role in modern electromagnetic and photonics systems. To date, the epsilon (ε)-near-zero (ENZ) is usually integrated with the low Q-factor resonant metasurface to achieve active devices, and enhance the light-matter interaction significantly at the nanoscale. However, the low Q-factor resonance may limit the optical modulation. Less work has been focused on the optical modulation in the low-loss and high Q-factor metasurfaces. Recently, the emerging optical bound states in the continuum (BICs) provides an effective way for achieving high Q-factor resonators. In this work, we numerically demonstrate a tunable quasi-BICs (QBICs) by integrating a silicon metasurface with ENZ ITO thin film. Such a metasurface is composed of five square holes in a unit cell, and hosts multiple BICs by engineering the position of centre hole. We also reveal the nature of these QBICs by performing multipole decomposition and calculating near field distribution. Thanks to the large tunability of ITO's permittivity by external bias and high-Q factor enabled by QBICs, we demonstrate an active control on the resonant peak position and intensity of transmission spectrum by integrating ENZ ITO thin films with QBICs supported by silicon metasurfaces. We find that all QBICs show excellent performance on modulating the optical response of such a hybrid structure. The modulation depth can be up to 14.8 dB. We also investigate how the carrier density of ITO film influence the near-field trapping and far-field scattering, which in turn influence the performance of optical modulation based on this structure. Our results may find promising applications in developing active high-performance optical devices.

JNK initiates Beclin-1 dependent autophagic cell death against Akt activation.

ABT-199, a specific inhibitor of the Bcl-2 protein, is widely used in clinical trials for hematological tumors and rarely applied to the research of solid tumors. In this study, we used Bax/Bak double knockout (KO) and knockdown (KD) cells as the model and found that ABT-199 initiated autophagic cell death independent of Bax and Bak. ABT-199 initiated Beclin-1-dependent autophagy, which led to cell death. Furthermore, inactivated Akt released Beclin-1 from the 14-3-3 protein through a change in the phosphorylation state of Beclin-1 in ABT-199-treated cells. Moreover, JNK antagonized the function of Akt in Beclin-1-mediated autophagy by phosphorylating the 14-3-3 protein. Phosphorylated 14-3-3 exhibited a decreased interaction with Beclin-1. Therefore, ABT-199 activated the JNK-Akt-14-3-3 signaling pathway to mediate the Beclin-1-dependent autophagic death of Bax/Bak KO and KD cells. These findings may extend the therapeutic application of ABT-199 to colon cancer, particularly apoptosis-deficient tumors.

Application of 3D printed pelvic fracture related urethra and surrounding tissue as preoperative planning model.

OBJECTIVE: Urethral stenosis caused by pelvic fracture urethral injury (PFUI) is a complex urological disease, especially for the redo cased. However, to find the proximal end of the posterior urethra, and to avoid injury to the rectum and to forecast to remove the inferior pubic margin are two key points for a successful surgery. These steps can be challenging for even the most experienced urologists. This study is to describe a new technique for understanding the three-dimensional (3D) anatomy of the urethra, which will also aid in surgical planning and simplify urethroplasty. MATERIALS AND METHODS: Three patients underwent routine urethroscopy, X ray urethrography and contrast CT urethrography. The 3D images were then reconstructed, and the data were transmitted to a 3D printer. 3D models were printed with polyacrylic acid to simulate the anatomical structure and relationship of urethral stenosis with pubic symphysis and rectum. Various diagnosis methods were compared with the condition in surgery. The patients and trainee questionnaires were performed. RESULTS: Three models of urethral CT were obtained. These models were presented to patients and trainee doctors along with routine urethroscopy, urethrography, and urethral CT. The scores of patients and trainee question forms demonstrated that the 3D printed urethral stenosis model of pelvic fracture has obvious advantages in urethral adjacency and ease of understanding. The 3D printed urethras were easy to show the pubic symphysis and simulate its excision and exposure of urethra. The model could show the precise distance from urethra to rectum to prevent the rectum injury in surgery. CONCLUSIONS: 3D printing technology can be applied to the preoperative evaluation of urethral stenosis caused by PFUI. It can be auxiliary to understand the anatomical structure of the posterior urethra, the direction of urethral displacement, protecting the rectum and the forecasting for pubectomy. It is especially helpful for the accurate preoperative planning of some complex urethral stenosis and redo cases.

Cardiac-Specific Expression of Cre Recombinase Leads to Age-Related Cardiac Dysfunction Associated with Tumor-like Growth of Atrial Cardiomyocyte and Ventricular Fibrosis and Ferroptosis.

Transgenic expression of Cre recombinase driven by a specific promoter is normally used to conditionally knockout a gene in a tissue- or cell-type-specific manner. In αMHC-Cre transgenic mouse model, expression of Cre recombinase is controlled by the myocardial-specific α-myosin heavy chain (αMHC) promoter, which is commonly used to edit myocardial-specific genes. Toxic effects of Cre expression have been reported, including intro-chromosome rearrangements, micronuclei formation and other forms of DNA damage, and cardiomyopathy was observed in cardiac-specific Cre transgenic mice. However, mechanisms associated with Cardiotoxicity of Cre remain poorly understood. In our study, our data unveiled that αMHC-Cre mice developed arrhythmias and died after six months progressively, and none of them survived more than one year. Histopathological examination showed that αMHC-Cre mice had aberrant proliferation of tumor-like tissue in the atrial chamber extended from and vacuolation of ventricular myocytes. Furthermore, the αMHC-Cre mice developed severe cardiac interstitial and perivascular fibrosis, accompanied by significant increase of expression levels of MMP-2 and MMP-9 in the cardiac atrium and ventricular. Moreover, cardiac-specific expression of Cre led to disintegration of the intercalated disc, along with altered proteins expression of the disc and calcium-handling abnormality. Comprehensively, we identified that the ferroptosis signaling pathway is involved in heart failure caused by cardiac-specific expression of Cre, on which oxidative stress results in cytoplasmic vacuole accumulation of lipid peroxidation on the myocardial cell membrane. Taken together, these results revealed that cardiac-specific expression of Cre recombinase can lead to atrial mesenchymal tumor-like growth in the mice, which causes cardiac dysfunction, including cardiac fibrosis, reduction of the intercalated disc and cardiomyocytes ferroptosis at the age older than six months in mice. Our study suggests that αMHC-Cre mouse models are effective in young mice, but not in old mice. Researchers need to be particularly careful when using αMHC-Cre mouse model to interpret those phenotypic impacts of gene responses. As the Cre-associated cardiac pathology matched mostly to that of the patients, the model could also be employed for investigating age-related cardiac dysfunction.

The genome of the rice planthopper egg parasitoid wasps Anagrus nilaparvatae casts light on the chemo- and mechanosensation in parasitism.

BACKGROUND: Mymaridae is an ancient insect group and is a basal lineage of the superfamily Chalcidoidea. Species of Mymaridae have great potential for biological control. Anagrus nilaparvatae, a representative species of Mymaridae, is ideal for controlling rice planthopper due to its high rate of parasitism and ability to find hosts efficiently in paddy ridges and fields. RESULTS: Using both PacBio single-molecule real-time and Illumina sequencing, we sequenced and assembled the whole genome of A. nilaparvatae, a first for the family Mymaridae. The assembly consists of 394 scaffolds, totaling 488.8 Mb. The assembly is of high continuity and completeness, indicated by the N50 value of 25.4 Mb and 98.2% mapping rate of Benchmarking Universal Single-Copy Orthologs. In total, 16,894 protein-coding genes in the genome were annotated. A phylogenomic tree constructed for A. nilaparvatae and other 12 species of Hymenoptera confirmed that the family Mymaridae is sister to all remaining chalcidoids. The divergence time between A. nilaparvatae and the other seven Chalcidoidea species was dated at ~ 126.9 Mya. Chemoreceptor and mechanoreceptor genes are important in explaining parasitic behavior. We identified 17 odorant binding proteins, 11 chemosensory proteins, four Niemann-Pick type C2 proteins, 88 olfactory receptors, 12 gustatory receptors, 22 ionotropic receptors and 13 sensory neuron membrane proteins in the genome of A. nilaparvatae, which are associated with the chemosensory functions. Strikingly, there is only one pickpocket receptors and nine transient receptor potential genes in the genome that have a mechanosensory function. CONCLUSIONS: We obtained a high-quality genome assembly for A. nilaparvatae using PacBio single-molecule real-time sequencing, which provides phylogenomic insights for its evolutionary history. The small numbers of chemo- and mechanosensory genes in A. nilaparvatae indicate the species-specific host detection and oviposition behavior of A. nilaparvatae might be regulated by relatively simple molecular pathways.

Toward Smart Home Authentication Using PUF and Edge-Computing Paradigm.

The smart home is a crucial embodiment of the internet of things (IoT), which can facilitate users to access smart home services anytime and anywhere. Due to the limited resources of cloud computing, it cannot meet users' real-time needs. Therefore, edge computing emerges as the times require, providing users with better real-time access and storage. The application of edge computing in the smart home environment can enable users to enjoy smart home services. However, users and smart devices communicate through public channels, and malicious attackers may intercept information transmitted through public channels, resulting in user privacy disclosure. Therefore, it is a critical issue to protect the secure communication between users and smart devices in the smart home environment. Furthermore, authentication protocols in smart home environments also have some security challenges. In this paper, we propose an anonymous authentication protocol that applies edge computing to the smart home environment to protect communication security between entities. To protect the security of smart devices, we embed physical unclonable functions (PUF) into each smart device. Real-or-random model, informal security analysis, and ProVerif are adopted to verify the security of our protocol. Finally, we compare our protocol with existing protocols regarding security and performance. The comparison results demonstrate that our protocol has higher security and slightly better performance.

The Prognostic Significance of FKBP1A and Its Related Immune Infiltration in Liver Hepatocellular Carcinoma.

Liver hepatocellular carcinoma (LIHC) remains a global health challenge with poor prognosis and high mortality. FKBP1A was first discovered as a receptor for the immunosuppressant drug FK506 in immune cells and is critical for various tumors and cancers. However, the relationships between FKBP1A expression, cellular distribution, tumor immunity, and prognosis in LIHC remain unclear. Here, we investigated the expression level of FKBP1A and its prognostic value in LIHC via multiple datasets including ONCOMINE, TIMER, GEPIA, UALCAN, HCCDB, Kaplan-Meier plotter, LinkedOmics, and STRING. Human liver tissue microarray was employed to analyze the characteristics of FKBP1A protein including the expression level and pathological alteration in cellular distribution. FKBP1A expression was significantly higher in LIHC and correlated with tumor stage, grade and metastasis. The expression level of the FKBP1A protein was also increased in LIHC patients along with its accumulation in endoplasmic reticulum (ER). High FKBP1A expression was correlated with a poor survival rate in LIHC patients. The analysis of gene co-expression and the regulatory pathway network suggested that FKBP1A is mainly involved in protein synthesis, metabolism and the immune-related pathway. FKBP1A expression had a significantly positive association with the infiltration of hematopoietic immune cells including B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells. Moreover, M2 macrophage infiltration was especially associated with a poor survival prognosis in LIHC. Furthermore, FKBP1A expression was significantly positively correlated with the expression of markers of M2 macrophages and immune checkpoint proteins such as PD-L1, CTLA-4, LAG3 and HAVCR2. Our study demonstrated that FKBP1A could be a potential prognostic target involved in tumor immune cell infiltration in LIHC.

An observational cohort study of bacterial co-infection and implications for empirical antibiotic therapy in patients presenting with COVID-19 to hospitals in North West London.

OBJECTIVES: To describe the prevalence and nature of bacterial co-infections in COVID-19 patients within 48 hours of hospital admission and assess the appropriateness of empirical antibiotic treatment they received. METHODS: In this retrospective observational cohort study, we included all adult non-pregnant patients who were admitted to two acute hospitals in North West London in March and April 2020 and confirmed to have COVID-19 infection within 2 days of admission. Results of microbiological specimens taken within 48 hours of admission were reviewed and their clinical significance was assessed. Empirical antibiotic treatment of representative patients was reviewed. Patient age, gender, co-morbidities, inflammatory markers at admission, admission to ICU and 30 day all-cause in-hospital mortality were collected and compared between patients with and without bacterial co-infections. RESULTS: Of the 1396 COVID-19 patients included, 37 patients (2.7%) had clinically important bacterial co-infection within 48 hours of admission. The majority of patients (36/37 in those with co-infection and 98/100 in selected patients without co-infection) received empirical antibiotic treatment. There was no significant difference in age, gender, pre-existing illnesses, ICU admission or 30 day all-cause mortality in those with and without bacterial co-infection. However, white cell count, neutrophil count and CRP on admission were significantly higher in patients with bacterial co-infections. CONCLUSIONS: We found that bacterial co-infection was infrequent in hospitalized COVID-19 patients within 48 hours of admission. These results suggest that empirical antimicrobial treatment may not be necessary in all patients presenting with COVID-19 infection, although the decision could be guided by high inflammatory markers.

Heterogeneous nutrient supply promotes maize growth and phosphorus acquisition: additive and compensatory effects of lateral roots and root hairs.

BACKGROUND AND AIMS: Root proliferation is a response to a heterogeneous nutrient distribution. However, the growth of root hairs in response to heterogeneous nutrients and the relationship between root hairs and lateral roots remain unclear. This study aims to understand the effects of heterogeneous nutrients on root hair growth and the trade-off between root hairs and lateral roots in phosphorus (P) acquisition. METHODS: Near-isogenic maize lines, the B73 wild type (WT) and the rth3 root hairless mutant, were grown in rhizoboxes with uniform or localized supply of 40 (low) or 140 (high) mg P kg-1 soil. RESULTS: Both WT and rth3 had nearly two-fold greater shoot biomass and P content under local than uniform treatment at low P. Significant root proliferation was observed in both WT and rth3 in the nutrient patch, with the WT accompanied by an obvious increase (from 0.7 to 1.2 mm) in root hair length. The root response ratio of rth3 was greater than that of WT at low P, but could not completely compensate for the loss of root hairs. This suggests that plants enhanced P acquisition through complementarity between lateral roots and root hairs, and thus regulated nutrient foraging and shoot growth. The disappearance of WT and rth3 root response differences at high P indicated that the P application reduced the dependence of the plants on specific root traits to obtain nutrients. CONCLUSIONS: In addition to root proliferation, the root response to a nutrient-rich patch was also accompanied by root hair elongation. The genotypes without root hairs increased their investment in lateral roots in a nutrient-rich patch to compensate for the absence of root hairs, suggesting that plants enhanced nutrient acquisition by regulating the trade-off of complementary root traits.

All-trans retinoic acid reduces cancer stem cell-like cell-mediated resistance to gefitinib in NSCLC adenocarcinoma cells.

BACKGROUND: The enrichment of cancer stem cell-like cells (CSCs) has been considered to be responsible for tumor progression after an initial response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) in patients with non-small cell lung adenocarcinoma (NSCLC/ADC). CSCs with ALDH1A1bright /CD44high expression contribute to the TKIs resistance in NSCLC/ADC cells. All-trans retinoic acid (ATRA) has been shown to be a potential targeted therapy against CSCs due to its ability to inhibit ALDH1A1 activity. We therefore investigated whether ATRA could circumvent the resistance to improve the response to gefitinib in NSCLC/ADC cells. METHODS: Treatment of NSCLC/ADC A549 and H1650 cells with gefitinib enriched the gefitinib surviving cells (GSCs). The expression of ALDH1A1 and CD44 and the IC50 values for gefitinib were determined by flow cytometry (FCM) and crystal violet assay in GSCs and ATRA-treated GSCs, respectively. Using DEAB as the positive control, direct inhibitory effect of ATRA on ALDH1A1 activity was determined by ALDEFLUOR assay, RESULTS: GSCs showed higher expression of ALDH1A1 and CD44 and IC50 values for gefitinib than their respective parental cells, suggesting that gefitinib can lead to propagation of CSC-enriched gefitinib-resistant cells. Treatment with ATRA was found to significantly reduce the increased expression of ALDH1A1 and CD44 and the IC50 values for gefitinib in A549GSC and H1650GSC cells, and ATRA could directly inhibit active ALDH1A1 as compared to DEAB. CONCLUSION: Our findings suggest that combination treatment with ATRA prevents gefitinib-induced enrichment of ALDH1A1bright/CD44high CSCs and enhances gefitinib-induced growth inhibition of NSCLC/ADC cells.

IGRNet: A Deep Learning Model for Non-Invasive, Real-Time Diagnosis of Prediabetes through Electrocardiograms.

The clinical symptoms of prediabetes are mild and easy to overlook, but prediabetes may develop into diabetes if early intervention is not performed. In this study, a deep learning model-referred to as IGRNet-is developed to effectively detect and diagnose prediabetes in a non-invasive, real-time manner using a 12-lead electrocardiogram (ECG) lasting 5 s. After searching for an appropriate activation function, we compared two mainstream deep neural networks (AlexNet and GoogLeNet) and three traditional machine learning algorithms to verify the superiority of our method. The diagnostic accuracy of IGRNet is 0.781, and the area under the receiver operating characteristic curve (AUC) is 0.777 after testing on the independent test set including mixed group. Furthermore, the accuracy and AUC are 0.856 and 0.825, respectively, in the normal-weight-range test set. The experimental results indicate that IGRNet diagnoses prediabetes with high accuracy using ECGs, outperforming existing other machine learning methods; this suggests its potential for application in clinical practice as a non-invasive, prediabetes diagnosis technology.