Apigenin inhibits tumor angiogenesis by hindering microvesicle biogenesis via ARHGEF1.

Extracellular vesicles are essential for intercellular communication and are involved in tumor progression. Inhibiting the direct release of extracellular vesicles seems to be an effective strategy in inhibiting tumor progression, but lacks of investigation. Here, we report a natural flavonoid compound, apigenin, could significantly inhibit the growth of hepatocellular carcinoma by preventing microvesicle secretion. Mechanistically, apigenin primarily targets the guanine nucleotide exchange factor ARHGEF1, inhibiting the activity of small G protein Cdc42, which is essential in regulating the release of microvesicles from tumor cells. In turn, this inhibits tumor angiogenesis related to VEGF90K transported on microvesicles, ultimately impeding tumor progression. Collectively, these findings highlight the therapeutic potential of apigenin and shed light on its anticancer mechanisms through inhibiting microvesicle biogenesis, providing a solid foundation for the refinement and practical application of apigenin.

Comprehensive single-cell analysis deciphered microenvironmental dynamics and immune regulator olfactomedin 4 in pathogenesis of gallbladder cancer.

OBJECTIVE: Elucidating complex ecosystems and molecular features of gallbladder cancer (GBC) and benign gallbladder diseases is pivotal to proactive cancer prevention and optimal therapeutic intervention. DESIGN: We performed single-cell transcriptome analysis on 230 737 cells from 15 GBCs, 4 cholecystitis samples, 3 gallbladder polyps, 5 gallbladder adenomas and 16 adjacent normal tissues. Findings were validated through large-scale histological assays, digital spatial profiler multiplexed immunofluorescence (GeoMx), etc. Further molecular mechanism was demonstrated with in vitro and in vivo studies. RESULTS: The cell atlas unveiled an altered immune landscape across different pathological states of gallbladder diseases. GBC featured a more suppressive immune microenvironment with distinct T-cell proliferation patterns and macrophage attributions in different GBC subtypes. Notably, mutual exclusivity between stromal and immune cells was identified and remarkable stromal ecosystem (SC) heterogeneity during GBC progression was unveiled. Specifically, SC1 demonstrated active interaction between Fibro-iCAF and Endo-Tip cells, correlating with poor prognosis. Moreover, epithelium genetic variations within adenocarcinoma (AC) indicated an evolutionary similarity between adenoma and AC. Importantly, our study identified elevated olfactomedin 4 (OLFM4) in epithelial cells as a central player in GBC progression. OLFM4 was related to T-cell malfunction and tumour-associated macrophage infiltration, leading to a worse prognosis in GBC. Further investigations revealed that OLFM4 upregulated programmed death-ligand 1 (PD-L1) expression through the MAPK-AP1 axis, facilitating tumour cell immune evasion. CONCLUSION: These findings offer a valuable resource for understanding the pathogenesis of gallbladder diseases and indicate OLFM4 as a potential biomarker and therapeutic target for GBC.

Bortezomib in previously treated phosphatase and tension homology-deficient patients with advanced intrahepatic cholangiocarcinoma: An open-label, prospective and single-centre phase II trial.

INTRODUCTION: Intrahepatic cholangiocarcinoma (ICC) is characterized by a dismal prognosis with limited therapeutic alternatives. To explore phosphatase and tension homolog (PTEN) as a biomarker for proteasome inhibition in ICC, we conducted a phase II trial to assess the second-line efficacy of bortezomib in PTEN-deficient advanced ICC patients. METHODS: A total of 130 patients with advanced ICC in our centre were screened by PTEN immunohistochemical staining between 1 July 2017, and 31 December 2021, and 16 patients were ultimately enrolled and treated with single-agent bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11 of a 21-day cycle. The primary endpoint was the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors v1.1. RESULTS: The median follow-up was 6.55 months (95% confidence interval [CI]: 0.7-19.9 months). Among the 16 enrolled patients, the ORR was 18.75% (3/16) and the disease control rate was 43.75% (7/16). The median progress-free survival was 2.95 months (95% CI: 2.1-5.1 months) and the median overall survival (mOS) was 7.2 months (95% CI: 0.7-21.6 months) in the intent-to-treat-patients. Treatment-related adverse events of any grade were reported in 16 patients, with thrombopenia being the most common toxicity. Patients with PTEN staining scores of 0 were more likely to benefit from bortezomib than those with staining scores > 0. CONCLUSIONS: Bortezomib yielded an encouraging objective response and a favourable OS as a second-line agent in PTEN-deficient ICC patients. Our findings suggest bortezomib as a promising therapeutic option for patients with PTEN-deficient ICC. HIGHLIGHTS: There is a limited strategy for the second-line option of intrahepatic cholangiocarcinoma (ICC). This investigator-initiated phase 2 study evaluated bortezomib in ICC patients with phosphatase and tension homology deficiency. The overall response rate was 18.75% and the overall survival was 7.2 months in the intent-to-treat cohort. These results justify further developing bortezomib in ICC patients with PTEN deficiency.

A study of extractive summarization of long documents incorporating local topic and hierarchical information.

In recent years, the transformer-based language models have achieved remarkable success in the field of extractive text summarization. However, there are still some limitations in this kind of research. First, the transformer language model usually regards the text as a linear sequence, ignoring the inherent hierarchical structure information of the text. Second, for long text data, traditional extractive models often focus on global topic information, which poses challenges in how they capturing and integrating local contextual information within topic segments. To address these issues, we propose a long text extractive summarization model that employs a local topic information extraction module and a text hierarchical extraction module to capture the local topic information and document's hierarchical structure information of the original text. Our approach enhances the ability to determine whether a sentence belongs to the summary. In this experiment, ROUGE score is used as the experimental evaluation index, and evaluates the model on three large public datasets. Through experimental validation, the model demonstrates superior performance in terms of ROUGE-1, ROUGE-2, and ROUGE-L scores compared to current mainstream summarization models, affirming the effectiveness of incorporating local topic information and document hierarchical structure into the model.

Co-contamination and interactions of multiple mycotoxins and heavy metals in rice, maize, soybeans, and wheat flour marketed in Shanghai City.

Mycotoxins and heavy metals extensively contaminate grains and grain products, posing severe health risks. This work implements validated ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and inductively coupled plasma mass spectrometry (ICP-MS) methods to quantify the concentration of 12 mycotoxins and five heavy metals in rice, maize, soybeans, and wheat flour samples marketed in Shanghai. The mixed contamination characteristics were analyzed using correlation cluster analysis and co-contamination index, and the probabilities of all cross combinations of contaminations were analyzed using a self-designed JAVA language program. The results showed that grains and grain products were frequently contaminated with both mycotoxins and heavy metals, mostly with deoxynivalenol (DON), 3-acetyl-deoxynivalenol (3-ADON), 15-acetyl-deoxynivalenol (15-ADON), ochratoxin A (OTA), aflatoxins, fumonisin B1 (FB1), fumonisin B2 (FB2), fumonisin B3 (FB3), arsenic (As), chromium (Cr) and cadmium (Cd). All the samples (100 %) were contaminated with two or more contaminants, and 77.3 % of the samples were co-contaminated with more than four contaminants. In cereals and cereal products, the following combinations were closely associated: (FB3 +3-ADON), (FB1 +As), (FB1 +FB2), (DON+FB1), (DON+Cd), (As+Cd), (DON+Cd+As), (FB1 +FB2 +As), and (DON+3-ADON+15-ADON). The results indicated that mycotoxins and heavy metals frequently co-occurred in Shanghai grains and grain products, and they provided primary data for safety assessments, early warnings, and regulatory measures on these contaminants to protect public health.

Allochthonous Trichoderma Isolates Boost Atractylodes lancea Herb Quality at the Cost of Rhizome Growth.

Atractylodes lancea is a perennial herb whose rhizome (AR) is a valuable traditional Chinese medicine with immense market demand. The cultivation of Atractylodes lancea faces outbreaks of root rot and deterioration in herb quality due to complex causes. Here, we investigated the effects of Trichoderma spp., well-known biocontrol agents and plant-growth-promoters, on ARs. We isolated Trichoderma strains from healthy ARs collected in different habitats and selected three T. harzianum strains (Th2, Th3 and Th4) with the strongest antagonizing effects on root rot pathogens (Fusarium spp.). We inoculated geo-authentic A. lancea plantlets with Th2, Th3 and Th4 and measured the biomass and quality of 70-day-old ARs. Th2 and Th3 promoted root rot resistance of A. lancea. Th2, Th3 and Th4 all boosted AR quality: the concentration of the four major medicinal compounds in ARs (atractylon, atractylodin, hinesol and ß-eudesmol) each increased 1.6- to 18.2-fold. Meanwhile, however, the yield of ARs decreased by 0.58- to 0.27-fold. Overall, Th3 dramatically increased the quality of ARs at a relatively low cost, namely lower yield, showing great potential for practical application. Our results showed selectivity between A. lancea and allochthonous Trichoderma isolates, indicating the importance of selecting specific microbial patches for herb cultivation.

Carbon Nanofiber Membranes Loaded with MXene@g-C3N4: Preparation and Photocatalytic Property.

In this study, a Ti3C2 MXene@g-C3N4 composite powder (TM-CN) was prepared by the ultrasonic self-assembly method and then loaded onto a carbon nanofiber membrane by the self-assembly properties of MXene for the treatment of organic pollutants in wastewater. The characterization of the TM-CN and the C-TM-CN was conducted via X-ray diffraction (XRD), scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), and Fourier transform infrared spectrometer (FTIR) to ascertain the successful modification. The organic dye degradation experiments demonstrated that introducing an appropriate amount of Ti3C2 MXene resulted in the complete degradation of RhB within 60 min, three times the photocatalytic efficiency of a pure g-C3N4. The C-TM-CN exhibited the stable and outstanding photocatalytic degradation of the RhB solution over a wide range of pH values, indicating the characteristics of the photodegradation of organic pollutants in a wide range of aqueous environments. Furthermore, the results of the cyclic degradation experiments demonstrated that the C-TM-CN composite film maintained a degradation efficiency of over 85% after five cycles, thereby confirming a notable improvement in its cyclic stability. Consequently, the C-TM-CN composite film exhibits excellent photocatalytic performance and is readily recyclable, making it an auspicious eco-friendly material in water environment remediation.

Infection with SARS-CoV-2 can cause pancreatic impairment.

Evidence suggests associations between COVID-19 patients or vaccines and glycometabolic dysfunction and an even higher risk of the occurrence of diabetes. Herein, we retrospectively analyzed pancreatic lesions in autopsy tissues from 67 SARS-CoV-2 infected non-human primates (NHPs) models and 121 vaccinated and infected NHPs from 2020 to 2023 and COVID-19 patients. Multi-label immunofluorescence revealed direct infection of both exocrine and endocrine pancreatic cells by the virus in NHPs and humans. Minor and limited phenotypic and histopathological changes were observed in adult models. Systemic proteomics and metabolomics results indicated metabolic disorders, mainly enriched in insulin resistance pathways, in infected adult NHPs, along with elevated fasting C-peptide and C-peptide/glucose ratio levels. Furthermore, in elder COVID-19 NHPs, SARS-CoV-2 infection causes loss of beta (ß) cells and lower expressed-insulin in situ characterized by islet amyloidosis and necrosis, activation of α-SMA and aggravated fibrosis consisting of lower collagen in serum, an increase of pancreatic inflammation and stress markers, ICAM-1 and G3BP1, along with more severe glycometabolic dysfunction. In contrast, vaccination maintained glucose homeostasis by activating insulin receptor α and insulin receptor ß. Overall, the cumulative risk of diabetes post-COVID-19 is closely tied to age, suggesting more attention should be paid to blood sugar management in elderly COVID-19 patients.

Global research landscape on the contribution of de novo mutations to human genetic diseases over the past 20 years: bibliometric analysis.

As the contribution of de novo mutations (DNMs) to human genetic diseases has been gradually uncovered, analyzing the global research landscape over the past 20 years is essential. Because of the large and rapidly increasing number of publications in this field, understanding the current landscape of the contribution of DNMs in the human genome to genetic diseases remains a challenge. Bibliometric analysis provides an approach for visualizing these studies using information in published records in a specific field. This study aimed to illustrate the current global research status and explore trends in the field of DNMs underlying genetic diseases. Bibliometric analyses were performed using the Bibliometrix Package based on the R language version 4.1.3 and CiteSpace version 6.1.R2 software for publications from 2000 to 2021 indexed under the Web of Science Core Collection (WoSCC) about DNMs underlying genetic diseases on 17 September 2022. We identified 3435 records, which were published in 731 journals by 26,538 authors from 6052 institutes in 66 countries. There was an upward trend in the number of publications since 2013. The USA, China, and Germany contributed the majority of the records included. The University of Washington, Columbia University, and Baylor College of Medicine were the top-producing institutions. Evan E Eichler of the University of Washington, Stephan J Sanders of the Yale University School of Medicine, and Ingrid E Scheffer of the University of Melbourne were the most high-ranked authors. Keyword co-occurrence analysis suggested that DNMs in neurodevelopmental disorders and intellectual disabilities were research hotspots and trends. In conclusion, our data show that DNMs have a significant effect on human genetic diseases, with a noticeable increase in annual publications over the last 5 years. Furthermore, potential hotspots are shifting toward understanding the causative role and clinical interpretation of newly identified or low-frequency DNMs observed in patients.

[Mechanism and application prospects of microbial fertilizers in regulating quality formation of medicinal plants].

With the promotion of chemical fertilizer and pesticide reduction and green production of traditional Chinese medicines, microbial fertilizers have become a hot way to achieve the zero-growth of chemical fertilizers and pesticides, improve the yield and qua-lity of medicinal plants, maintain soil health, and promote the sustainable development of the planting industry of Chinese herbal medicines. Soil conditions and microenvironments are crucial to the growth, development, and quality formation of medicinal plants. Microbial fertilizers, as environmentally friendly fertilizers acting on the soil, can improve soil quality by replenishing organic matter and promoting the metabolism of beneficial microorganisms to improve the yield and quality of medicinal plants. In this regard, understanding the mechanism of microbial fertilizer in regulating the quality formation of medicinal plants is crucial for the development of herbal eco-agriculture. This study introduces the processes of microbial fertilizers in improving soil properties, participating in soil nutrient cycling, enhancing the resistance of medicinal plants, and promoting the accumulation of medicinal components to summarize the mechanisms and roles of bacterial fertilizers in regulating the quality formation of medicinal plants. Furthermore, this paper introduces the application of bacterial fertilizers in medicinal plants and makes an outlook on their development, with a view to providing a scientific basis for using microbial fertilizers to improve the quality of Chinese herbal medicines, improve the soil environment, promote the sustainable development of eco-agriculture of traditional Chinese medicine, and popularize the application of microbial fertilizers.

Cancer stem cell-immune cell crosstalk in the tumor microenvironment for liver cancer progression.

Crosstalk between cancer cells and the immune microenvironment is determinant for liver cancer progression. A tumor subpopulation called liver cancer stem cells (CSCs) significantly accounts for the initiation, metastasis, therapeutic resistance, and recurrence of liver cancer. Emerging evidence demonstrates that the interaction between liver CSCs and immune cells plays a crucial role in shaping an immunosuppressive microenvironment and determining immunotherapy responses. This review sheds light on the bidirectional crosstalk between liver CSCs and immune cells for liver cancer progression, as well as the underlying molecular mechanisms after presenting an overview of liver CSCs characteristic and their microenvironment. Finally, we discuss the potential application of liver CSCs-targeted immunotherapy for liver cancer treatment.

[Research progress in genetics of noise-induced hearing loss].

Noise-induced hearing loss（NIHL） is an acquired sensorineural hearing loss induced by long-term noise exposure. The susceptibility of exposed people may vary even in the same noise environment. With the development of sequencing techniques, genes related to oxidative stress, immunoinflammatory, ion homeostasis, energy metabolism, DNA damage repair and other mechanisms in NIHL have been reported continuously. And some genes may interact with noise exposure indexes. In this article, population studies on NIHL-related gene polymorphisms and gene-environment interactions in the past 20 years are reviewed, aimed to providing evidence for the construction of NIHL-related risk prediction models and the formulation of individualized interventions.

Experimental study on the impact of "IDS + JFCS" complex wetting agent on the characteristics of coal bodies.

As China's coal mines have transitioned to deep mining, the ground stress within the coal seams has progressively increased, resulting in reduced permeability and poor wetting ability of conventional wetting agents. Consequently, these agents have become inadequate in fulfilling the requirements for preventing washouts during deep mining operations. In response to the aforementioned challenges, a solution was proposed to address the issues by formulating a composite wetting agent. This composite wetting agent combines a conventional surfactant with a chelating agent called tetrasodium iminodisuccinate (IDS). By conducting a meticulous screening of surfactant monomer solutions, the ideal formulation for the composite wetting agent was determined by combining the monomer surfactant with IDS. Extensive testing, encompassing evaluations of the composite solution's apparent strain, contact angle measurements, and alterations in the oxygenated functional groups on the coal surface, led to the identification of the optimal composition. This composition consisted of IDS serving as the chelating agent and fatty alcohol polyoxyethylene ether (JFCS).Subsequent assessment of the physical and mechanical performance of the coal briquettes treated with the composite wetting agent revealed notable enhancements. These findings signify significant advancements in the field and hold promising implications. Following the application of the composite wetting agent, notable reductions were observed in the dry basis ash and dry basis full sulfur of coal. Additionally, the water content within the coal mass increased significantly, leading to a substantial enhancement in the wetting effect of the coal body. This enhanced wetting effect effectively mitigated the coal body's inclination towards impact, thereby offering technical support for optimizing water injection into coal seams and preventing as well as treating impact ground pressure.

Clinical and genetic architecture of a large cohort with auditory neuropathy.

Auditory neuropathy (AN) is a unique type of language developmental disorder, with no precise rate of genetic contribution that has been deciphered in a large cohort. In a retrospective cohort of 311 patients with AN, pathogenic and likely pathogenic variants of 23 genes were identified in 98 patients (31.5% in 311 patients), and 14 genes were mutated in two or more patients. Among subgroups of patients with AN, the prevalence of pathogenic and likely pathogenic variants was 54.4% and 56.2% in trios and families, while 22.9% in the cases with proband-only; 45.7% and 25.6% in the infant and non-infant group; and 33.7% and 0% in the bilateral and unilateral AN cases. Most of the OTOF gene (96.6%, 28/29) could only be identified in the infant group, while the AIFM1 gene could only be identified in the non-infant group; other genes such as ATP1A3 and OPA1 were identified in both infant and non-infant groups. In conclusion, genes distribution of AN, with the most common genes being OTOF and AIFM1, is totally different from other sensorineural hearing loss. The subgroups with different onset ages showed different genetic spectrums, so did bilateral and unilateral groups and sporadic and familial or trio groups.

Diverse functions of SOX9 in liver development and homeostasis and hepatobiliary diseases.

The liver is the central organ for digestion and detoxification and has unique metabolic and regenerative capacities. The hepatobiliary system originates from the foregut endoderm, in which cells undergo multiple events of cell proliferation, migration, and differentiation to form the liver parenchyma and ductal system under the hierarchical regulation of transcription factors. Studies on liver development and diseases have revealed that SRY-related high-mobility group box 9 (SOX9) plays an important role in liver embryogenesis and the progression of hepatobiliary diseases. SOX9 is not only a master regulator of cell fate determination and tissue morphogenesis, but also regulates various biological features of cancer, including cancer stemness, invasion, and drug resistance, making SOX9 a potential biomarker for tumor prognosis and progression. This review systematically summarizes the latest findings of SOX9 in hepatobiliary development, homeostasis, and disease. We also highlight the value of SOX9 as a novel biomarker and potential target for the clinical treatment of major liver diseases.

PTEN deficiency potentiates HBV-associated liver cancer development through augmented GP73/GOLM1.

BACKGROUND: Although hepatitis B virus (HBV) infection is a major risk factor for hepatic cancer, the majority of HBV carriers do not develop this lethal disease. Additional molecular alterations are thus implicated in the process of liver tumorigenesis. Since phosphatase and tensin homolog (PTEN) is decreased in approximately half of liver cancers, we investigated the significance of PTEN deficiency in HBV-related hepatocarcinogenesis. METHODS: HBV-positive human liver cancer tissues were checked for PTEN expression. Transgenic HBV, Alb-Cre and Ptenfl/fl mice were inter-crossed to generate WT, HBV, Pten-/- and HBV; Pten-/- mice. Immunoblotting, histological analysis and qRT-PCR were used to study these livers. Gp73-/- mice were then mated with HBV; Pten-/- mice to illustrate the role of hepatic tumor biomarker golgi membrane protein 73 (GP73)/ golgi membrane protein 1 (GOLM1) in hepatic oncogenesis. RESULTS: Pten deletion and HBV transgene synergistically aggravated liver injury, inflammation, fibrosis and development of mixed hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). GP73 was augmented in HBV; Pten-/- livers. Knockout of GP73 blunted the synergistic effect of deficient Pten and transgenic HBV on liver injury, inflammation, fibrosis and cancer development. CONCLUSIONS: This mixed HCC-ICC mouse model mimics liver cancer patients harboring HBV infection and PTEN/AKT signaling pathway alteration. Targeting GP73 is a promising therapeutic strategy for cancer patients with HBV infection and PTEN alteration.

A revamped rat reference genome improves the discovery of genetic diversity in laboratory rats.

The seventh iteration of the reference genome assembly for Rattus norvegicus-mRatBN7.2-corrects numerous misplaced segments and reduces base-level errors by approximately 9-fold and increases contiguity by 290-fold compared with its predecessor. Gene annotations are now more complete, improving the mapping precision of genomic, transcriptomic, and proteomics datasets. We jointly analyzed 163 short-read whole-genome sequencing datasets representing 120 laboratory rat strains and substrains using mRatBN7.2. We defined ∼20.0 million sequence variations, of which 18,700 are predicted to potentially impact the function of 6,677 genes. We also generated a new rat genetic map from 1,893 heterogeneous stock rats and annotated transcription start sites and alternative polyadenylation sites. The mRatBN7.2 assembly, along with the extensive analysis of genomic variations among rat strains, enhances our understanding of the rat genome, providing researchers with an expanded resource for studies involving rats.

AIF translocation into nucleus caused by Aifm1 R450Q mutation: generation and characterization of a mouse model for AUNX1.

Mutations in AIFM1, encoding for apoptosis-inducing factor (AIF), cause AUNX1, an X-linked neurologic disorder with late-onset auditory neuropathy (AN) and peripheral neuropathy. Despite significant research on AIF, there are limited animal models with the disrupted AIFM1 representing the corresponding phenotype of human AUNX1, characterized by late-onset hearing loss and impaired auditory pathways. Here, we generated an Aifm1 p.R450Q knock-in mouse model (KI) based on the human AIFM1 p.R451Q mutation. Hemizygote KI male mice exhibited progressive hearing loss from P30 onward, with greater severity at P60 and stabilization until P210. Additionally, muscle atrophy was observed at P210. These phenotypic changes were accompanied by a gradual reduction in the number of spiral ganglion neuron cells (SGNs) at P30 and ribbons at P60, which coincided with the translocation of AIF into the nucleus starting from P21 and P30, respectively. The SGNs of KI mice at P210 displayed loss of cytomembrane integrity, abnormal nuclear morphology, and dendritic and axonal demyelination. Furthermore, the inner hair cells and myelin sheath displayed abnormal mitochondrial morphology, while fibroblasts from KI mice showed impaired mitochondrial function. In conclusion, we successfully generated a mouse model recapitulating AUNX1. Our findings indicate that disruption of Aifm1 induced the nuclear translocation of AIF, resulting in the impairment in the auditory pathway.

Development of a Serum-Based MicroRNA Signature for Early Detection of Pancreatic Cancer: A Multicenter Cohort Study.

BACKGROUND: A grim prognosis of pancreatic cancer (PCa) was attributed to the difficulty in early diagnosis of the disease. AIMS: Identifying novel biomarkers for early detection of PCa is thus urgent to improve the overall survival rates of patients. METHODS: The study was performed firstly by identification of candidate microRNAs (miRNAs) in formalin-fixed, paraffin-embedded tissues using microarray profiles, and followed by validation in a serum-based cohort study to assess clinical utility of the candidates. In the cohorts, a total of 1273 participants from four centers were retrospectively recruited as two cohorts including training and validation cohort. The collected serum specimens were analyzed by real-time polymerase chain reaction. RESULTS: We identified 27 miRNAs expressed differentially in PCa tissues as compared to the benign. Of which, the top-four was selected as a panel whose diagnostic efficacy was fully assessed in the serum specimens. The panel exhibited superior to CA19-9, CA125, CEA and CA242 in discriminating patients with early stage PCa from healthy controls or non-PCa including chronic pancreatitis as well as pancreatic cystic neoplasms, with the area under the curves (AUC) of 0.971 (95% CI 0.956-0.987) and 0.924 (95% CI 0.899-0.949), respectively. Moreover, the panel eliminated interference from other digestive tumors with a specificity of 90.2%. CONCLUSIONS: A panel of four serum miRNAs was developed showing remarkably discriminative ability of early stage PCa from either healthy controls or other pancreatic diseases, suggesting it may be developed as a novel, noninvasive approach for early screening of PCa in clinic.

Identification of sleep and circadian alternative polyadenylation sites associated with APA-linked human brain disorders.

Sleep and circadian rhythm disruptions are comorbid features of many pathologies and can negatively influence numerous health conditions, including degenerative diseases, metabolic illnesses, cancer, and various neurological disorders. Genetic association studies linking sleep and circadian disturbances with disease susceptibility have mainly focused on changes in gene expression due to mutations, such as single-nucleotide polymorphisms. Thus, associations between sleep and/or circadian rhythm and alternative polyadenylation (APA), particularly in the context of other health challenges, are largely undescribed. APA is a process that generates various transcript isoforms from the same gene, resulting in effects on mRNA translation, stability, localization, and subsequent function. Here, we have identified unique APAs in rat brain that exhibit time-of-day-dependent oscillations in expression as well as APAs that are altered by sleep deprivation and the subsequent recovery period. Genes affected by APA usage include Mapt/Tau, Ntrk2, Homer1A, Sin3band Sorl. Sorl1 has two APAs which cycle with a 24 h period, one additional APA cycles with a 12 h period and one more that is reduced during recovery sleep. Finally, we compared sleep- or circadian-associated APAs with recently described APA-linked brain disorder susceptibility genes and found 46 genes in common.