Prediction of Prostate Cancer Risk Stratification Based on A Nonlinear Transformation Stacking Learning Strategy.

PURPOSE: Prostate cancer (PCa) is an epithelial malignancy that originates in the prostate gland and is generally categorized into low, intermediate, and high-risk groups. The primary diagnostic indicator for PCa is the measurement of serum prostate-specific antigen (PSA) values. However, reliance on PSA levels can result in false positives, leading to unnecessary biopsies and an increased risk of invasive injuries. Therefore, it is imperative to develop an efficient and accurate method for PCa risk stratification. Many recent studies on PCa risk stratification based on clinical data have employed a binary classification, distinguishing between low to intermediate and high risk. In this paper, we propose a novel machine learning (ML) approach utilizing a stacking learning strategy for predicting the tripartite risk stratification of PCa. METHODS: Clinical records, featuring attributes selected using the lasso method, were utilized with 5 ML classifiers. The outputs of these classifiers underwent transformation by various nonlinear transformers and were then concatenated with the lasso-selected features, resulting in a set of new features. A stacking learning strategy, integrating different ML classifiers, was developed based on these new features. RESULTS: Our proposed approach demonstrated superior performance, achieving an accuracy of 0.83 and an area under the receiver operating characteristic curve value of 0.88 in a dataset comprising 197 PCa patients with 42 clinical characteristics. CONCLUSION: This study aimed to improve clinicians' ability to rapidly assess PCa risk stratification while reducing the burden on patients. This was achieved by using artificial intelligence-related technologies as an auxiliary method for diagnosing PCa.

Transcriptome profiling reveals superovulation with the gonadotropin-releasing hormone agonist trigger impaired embryo implantation in mice.

Introduction: Superovulation is a critical step in assisted reproductive technology, but the use of human chorionic gonadotropin (hCG) as a trigger for superovulation can result in ovarian hyperstimulation. Thus, the use of Gonadotropin-releasing hormone agonist (GnRHa) trigger has been increasingly adopted, although it has been associated with a higher rate of pregnancy failure compared to natural cycles. This study aimed to investigate the effect of GnRHa trigger on embryo implantation in a mouse model. Methods: Mice in the superovulation (PG) group were administered 7.5 IU of PMSG, followed by the injection of 3.5 µg of GnRHa (Leuprorelin) 48 h later, while mice in the control group (CTR) mated naturally. We compared the number of oocytes, blastocysts, and corpus luteum between the two groups and the implantation sites after the transfer of natural blastocysts. Ovaries, uterus, and serum 2 and 4 days after mating were collected for qRT-PCR, transcriptome sequencing, and hormone assays. Results: The PG group had more oocytes, blastocysts, and corpus luteum after superovulation than the CTR group. However, the mRNA expression of leukemia inhibitory factor (Lif) and the number of implantation sites were reduced in the PG group. The ELISA assay revealed that superovulation increased ovarian estrogen secretion. The transcriptome analysis showed that superphysiological estrogen led to a response of the uterus to a high estrogen signal, resulting in abnormal endometrium and extracellular matrix remodeling and up-regulation of ion transport and inflammation-related genes. Conclusion: Our findings suggest that a combination of PMSG and GnRHa trigger impaired embryo implantation in mice, as the excessive uterine response to superphysiological estrogen levels can lead to the change of gene expression related to endometrial remodeling, abnormal expression of uterine ion transport genes and excessive immune-related genes.

An epitope encoded by uORF of RNF10 elicits a therapeutic anti-tumor immune response.

Tumor-specific antigens (TSAs) are crucial for tumor-specific immune response that reduces tumor burden and thus serve as important targets for immunotherapy. Identification of novel TSAs can provide new strategies for immunotherapies. In this study, we demonstrated that the upstream open reading frame (uORF) of RNF10 encodes an antigenic peptide (RNF10 uPeptide), capable of eliciting a T cell-mediated anti-tumor immune response. We initially demonstrated the immunogenicity of the RNF10 uPeptide in a CT26 tumor mouse model, by showing that its epitope was specifically recognized by CD8+ T cells. Vaccination of mice with the long form of the RNF10 uPeptide conferred strong anti-tumor activity. Next, we proved that the human RNF10 uORF could be translated. In addition, we predicted the binding of an RNF10 uPeptide epitope to HLA-A∗02:01 (HLA-A2). This HLA-A2-restricted epitope of the RNF10 uPeptide induced a potent specific human T cell response. Finally, we showed that an HLA-A2-restricted cytotoxic T cell (CTL) clone, derived from a pancreatic cancer patient, recognized the RNF10 uPeptide epitope (RLFGQQQRA) and lysed HLA-A2+ pancreatic carcinoma cells expressing the RNF10 uPeptide. These results indicate that the RNF10 uPeptide could be a promising target for pancreatic carcinoma immunotherapy.

Spatially resolved expression landscape and gene-regulatory network of human gastric corpus epithelium.

Molecular knowledge of human gastric corpus epithelium remains incomplete. Here, by integrated analyses using single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and single-cell assay for transposase accessible chromatin sequencing (scATAC-seq) techniques, we uncovered the spatially resolved expression landscape and gene-regulatory network of human gastric corpus epithelium. Specifically, we identified a stem/progenitor cell population in the isthmus of human gastric corpus, where EGF and WNT signaling pathways were activated. Meanwhile, LGR4, but not LGR5, was responsible for the activation of WNT signaling pathway. Importantly, FABP5 and NME1 were identified and validated as crucial for both normal gastric stem/progenitor cells and gastric cancer cells. Finally, we explored the epigenetic regulation of critical genes for gastric corpus epithelium at chromatin state level, and identified several important cell-type-specific transcription factors. In summary, our work provides novel insights to systematically understand the cellular diversity and homeostasis of human gastric corpus epithelium in vivo.

Development and validation of a clinic machine-learning nomogram for the prediction of risk stratifications of prostate cancer based on functional subsets of peripheral lymphocyte.

BACKGROUND: Non-invasive risk stratification contributes to the precise treatment of prostate cancer (PCa). In previous studies, lymphocyte subsets were used to differentiate between low-/intermediate-risk and high-risk PCa, with limited clinical value and poor interpretability. Based on functional subsets of peripheral lymphocyte with the largest sample size to date, this study aims to construct an easy-to-use and robust nomogram to guide the tripartite risk stratifications for PCa. METHODS: We retrospectively collected data from 2039 PCa and benign prostate disease (BPD) patients with 42 clinical characteristics on functional subsets of peripheral lymphocyte. After quality control and feature selection, clinical data with the optimal feature subset were utilized for the 10-fold cross-validation of five Machine Learning (ML) models for the task of predicting low-, intermediate- and high-risk stratification of PCa. Then, a novel clinic-ML nomogram was constructed using probabilistic predictions of the trained ML models via the combination of a multivariable Ordinal Logistic Regression analysis and the proposed feature mapping algorithm. RESULTS: 197 PCa patients, including 56 BPD, were enrolled in the study. An optimal subset with nine clinical features was selected. Compared with the best ML model and the clinic nomogram, the clinic-ML nomogram achieved the superior performance with a sensitivity of 0.713 (95% CI 0.573-0.853), specificity of 0.869 (95% CI 0.764-0.974), F1 of 0.699 (95% CI 0.557-0.841), and AUC of 0.864 (95% CI 0.794-0.935). The calibration curve and Decision Curve Analysis (DCA) indicated the predictive capacity and net benefits of the clinic-ML nomogram were improved. CONCLUSION: Combining the interpretability and simplicity of a nomogram with the efficacy and robustness of ML models, the proposed clinic-ML nomogram can serve as an insight tool for preoperative assessment of PCa risk stratifications, and could provide essential information for the individual diagnosis and treatment in PCa patients.

Effects of exogenous GnRH administration on lambing performance of oestrus-synchronized Kazak ewes during the breeding season.

The objective of this study was to investigate the effects of GnRH at insemination on lambing performance of Kazak ewes. Oestrus was synchronized in 774 adult Kazak ewes using an intravaginal sponge impregnated with flurogestone acetate. The sponge was left in the vagina for 12 days followed with an injection of 330 IU of eCG at sponge removal. Each ewe was inseminated twice at 48 h and 60 h after sponge removal. The treatment group (n = 387) was intramuscularly injected at the first insemination with a dose of 25 µg GnRH and the control group (n = 387) with saline solution. The results showed that GnRH administration significantly decreased the fertility rate. In addition, significant differences were observed between the two groups in terms of the twin birth rate, the abortion rate and the litter size. In conclusion, GnRH administration at insemination was not recommended in Kazak ewes undergoing the fixed time artificial insemination during the breeding season. The breed may be a critical determinant of the potential for the exploitation of GnRH application in sheep breeding programmes.

Establishment and characterization of adult human gastric epithelial progenitor-like cell lines.

OBJECTIVE: Human gastric epithelial stem/progenitor cells are important for stomach homeostasis; however, the in vitro culture system of these cells remains immature. Although three-dimensional (3D) organoid culture has fundamentally changed the in vitro study of gastrointestinal tract, its use is limited by inaccessible luminal compartment, and difficulties of imaging and manipulation. To overcome these limitations of 3D organoid culture system, we established adult human gastric epithelial progenitor-like (hGEPL) cell lines using a novel robust monolayer cell culture system. MATERIALS AND METHODS: We established an in vitro gel-based monolayer culture system for normal human adult gastric epithelium, and compared it with traditional two-dimensional (2D) and 3D organoid culture systems using transcriptomics, immunofluorescence and cell viability experiments. At the same time, we used single-cell transcriptomics to compare the differences of the hGEPL cells in conditioned medium (Cond.) and in chemically defined medium (Chem.), the two most common media for organoid culture, in maintaining the stemness and proliferative activity of hGEPL cells. Finally, we explored the role of key niche factors in inducing hGEPL cell differentiation. RESULTS: The hGEPL cells were similar to the in vivo gastric epithelial stem/progenitor cells, which could stably proliferate in culture for a long time. Based on the established culture system, we explored signalling pathways that were important for the homeostasis of hGEPL cells. We found that after blocking the WNT signalling pathway or activating the BMP signalling pathway, hGEPL cells could differentiate into mucous surface cells. CONCLUSION: Our culture system of hGEPL cells from adults is robust and easy to operate, and has the transformative potential of personalized and precision medicine, laying a solid foundation for studying the self-renewal and differentiation potentials of gastric epithelial stem/progenitor cells as well as modelling of related gastric diseases.

Endoscopic and pathohistologic features of early gastric signet ring cell carcinoma presented as elevated type: A case report.

Background: Almost all early gastric signet ring cell carcinomas (SRCCs) are the flat or depressed type, and the elevated type is rare. Here, we report the endoscopic and pathohistologic features of a rare case of SRCCs presented as the elevated type. Case presentation: A 54-year-old man underwent esophagogastroduodenoscopy in our hospital because of intermittent upper abdominal pain for 6 years. White light endoscopy revealed an elevated lesion that is smooth and reddish and covered with normal mucosa and looked like a polyp. Magnifying endoscopy with narrow-band imaging showed broadened intervening parts, an elongated pit, and a dense microvascular network with focal irregularity. The lesion was considered as early gastric cancer and completely resected with endoscopic submucosal dissection. Pathohistological examination confirmed that the lesion was pure early SRCC that was limited within the mucosal lamina propria (T1a). Conclusion: Elevated pure gastric SRCC is rare. This is a report of early pure gastric SRCC presented as the elevated type and the description of its endoscopic and pathohistologic features, which will contribute to the early detection of gastric SRCC.

Case report: New subtype of gastric adenocarcinoma arising from an H. pylori infection-negative stomach: Foveolar epithelium and mucous neck cell-mixed type adenocarcinoma.

The characteristics of Helicobacter pylori (H. pylori) infection-negative gastric cancer have not been well documented because of its rarity, despite several types of H. pylori infection-negative gastric cancers being reported. In this report, we describe a case of early gastric cancer that developed without H. pylori infection with characteristic magnifying narrow-band imaging and novel histological findings. The difficulty in making an accurate diagnosis and differential diagnosis is highlighted, with the goal of providing more clinical experience for the diagnosis of H. pylori infection-negative gastric cancer.

Single-cell genomic and transcriptomic landscapes of primary and metastatic colorectal cancer tumors.

BACKGROUND: Colorectal cancer (CRC) ranks as the second-leading cause of cancer-related death worldwide with metastases being the main cause of cancer-related death. Here, we investigated the genomic and transcriptomic alterations in matching adjacent normal tissues, primary tumors, and metastatic tumors of CRC patients. METHODS: We performed whole genome sequencing (WGS), multi-region whole exome sequencing (WES), simultaneous single-cell RNA-Seq, and single-cell targeted cDNA Sanger sequencing on matching adjacent normal tissues, primary tumors, and metastatic tumors from 12 metastatic colorectal cancer patients (n=84 for genomes, n=81 for exomes, n=9120 for single cells). Patient-derived tumor organoids were used to estimate the anti-tumor effects of a PPAR inhibitor, and self-renewal and differentiation ability of stem cell-like tumor cells. RESULTS: We found that the PPAR signaling pathway was prevalently and aberrantly activated in CRC tumors. Blocking of PPAR pathway both suppressed the growth and promoted the apoptosis of CRC organoids in vitro, indicating that aberrant activation of the PPAR signaling pathway plays a critical role in CRC tumorigenesis. Using matched samples from the same patient, distinct origins of the metastasized tumors between lymph node and liver were revealed, which was further verified by both copy number variation and mitochondrial mutation profiles at single-cell resolution. By combining single-cell RNA-Seq and single-cell point mutation identification by targeted cDNA Sanger sequencing, we revealed important phenotypic differences between cancer cells with and without critical point mutations (KRAS and TP53) in the same patient in vivo at single-cell resolution. CONCLUSIONS: Our data provides deep insights into how driver mutations interfere with the transcriptomic state of cancer cells in vivo at a single-cell resolution. Our findings offer novel knowledge on metastatic mechanisms as well as potential markers and therapeutic targets for CRC diagnosis and therapy. The high-precision single-cell RNA-seq dataset of matched adjacent normal tissues, primary tumors, and metastases from CRCs may serve as a rich resource for further studies.

Serum miR-21 predicts the prognosis of patients with primary gastrointestinal diffuse large B-cell lymphoma.

BACKGROUND: Primary gastrointestinal diffuse large B-cell lymphoma (PGI-DLBCL) lacks specific clinical manifestations and its malignancy renders prognostication and choice of treatment strategy difficult. The aim of this study was to evaluate microRNA (miR)-21 as potential non-invasive biomarkers for prognosis in PGI-DLBCL patients. METHODS: Serum miR-21 expression in de novo PGI-DLBCL patients, consecutively enrolled for this study, was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Relative expression was calculated using the comparative Ct method. Statistical significance was determined using the Mann-Whitney rank sum and Fisher's exact test. Survival analysis was conducted using the Kaplan-Meier method. RESULTS: Compared with healthy controls, serum miR-21 levels were significantly elevated in the PGI-DLBCL patients (n=156). The high expression level of serum miR-21 at diagnosis was associated with worse progression-free survival (PFS) (30 (9-42) vs 42 (12-52) months in high and low miR-21 groups) and overall survival (OS) (35 (15-52) vs 48 (17-61) months in high and low miR-21 groups) and was an independent risk factor for PFS and OS (hazard ratios 4.345 and 3.311, respectively). Furthermore, Bcl-2, Bcl-6 and Ki-67 were independently and positively associated with miR-21 expression. CONCLUSIONS: Our results suggest that miR-21 is a potential prognostic marker to predict clinical outcomes in PGI-DLBCL patients and a high miR-21 level is associated with poor outcomes.

Heterogeneous interface in hollow ferroferric oxide/ iron phosphide@carbon spheres towards enhanced Li storage.

Heterogeneous interface and structural engineering play important roles for electrochemical performance of lithium-ion batteries. Herein, heterostructures of hollow Fe3O4/FeP spheres coated with carbon shell (H-Fe3O4/FeP@C) are designed to enhance lithium storage performance. As bifunctional anode materials, the H-Fe3O4/FeP@C spheres show the good rate performance with 458.4 mAh g-1 at 5 A g-1 and long-cyclic performance (630.2 mAh g-1 at 2.0 A g-1 after 1000 cycles). Density functional theory calculations demonstrate that the heterogeneous interfaces from (311) plane of Fe3O4 and (002) plane of FeP possess high charge density and distinct metallic character, which can improve the conductivity, increase the adsorption energy, provide more active sites and reduce the transfer barrier of ions and electrons. Besides, hollow structure of H-Fe3O4/FeP@C not only alleviates the volume expansion during lithiation/delithiation process but also shortens the diffusion distance of Li ions. In addition, the ex-situ X-ray diffraction and X-ray photoelectron spectroscopy are used to reveal the electrochemical Li storage mechanisms of H-Fe3O4/FeP@C. This work provides a novel route for design and preparation of Fe-based heterostructures for various energy storage systems in the future.

Integrated single-cell multiomics analysis reveals novel candidate markers for prognosis in human pancreatic ductal adenocarcinoma.

The epigenomic abnormality of pancreatic ductal adenocarcinoma (PDAC) has rarely been investigated due to its strong heterogeneity. Here, we used single-cell multiomics sequencing to simultaneously analyze the DNA methylome, chromatin accessibility and transcriptome in individual tumor cells of PDAC patients. We identified normal epithelial cells in the tumor lesion, which have euploid genomes, normal patterns of DNA methylation, and chromatin accessibility. Using all these normal epithelial cells as controls, we determined that DNA demethylation in the cancer genome was strongly enriched in heterochromatin regions but depleted in euchromatin regions. There were stronger negative correlations between RNA expression and promoter DNA methylation in cancer cells compared to those in normal epithelial cells. Through in-depth integrated analyses, a set of novel candidate biomarkers were identified, including ZNF667 and ZNF667-AS1, whose expressions were linked to a better prognosis for PDAC patients by affecting the proliferation of cancer cells. Our work systematically revealed the critical epigenomic features of cancer cells in PDAC patients at the single-cell level.

Deep multimodal learning for lymph node metastasis prediction of primary thyroid cancer.

Objective. The incidence of primary thyroid cancer has risen steadily over the past decades because of overdiagnosis and overtreatment through the improvement in imaging techniques for screening, especially in ultrasound examination. Metastatic status of lymph nodes is important for staging the type of primary thyroid cancer. Deep learning algorithms based on ultrasound images were thus developed to assist radiologists on the diagnosis of lymph node metastasis. The objective of this study is to integrate more clinical context (e.g., health records and various image modalities) into, and explore more interpretable patterns discovered by, deep learning algorithms for the prediction of lymph node metastasis in primary thyroid cancer patients.Approach. A deep multimodal learning network was developed in this study with a novel index proposed to compare the contribution of different modalities when making the predictions.Main results. The proposed multimodal network achieved an average F1 score of 0.888 and an average area under the receiver operating characteristic curve (AUC) value of 0.973 in two independent validation sets, and the performance was significantly better than that of three single-modality deep learning networks. Moreover, among three modalities used in this study, the deep multimodal learning network relied generally more on image modalities than the data modality of clinic records when making the predictions.Significance. Our work is beneficial to prospective clinic trials of radiologists on the diagnosis of lymph node metastasis in primary thyroid cancer, and will better help them understand how the predictions are made in deep multimodal learning algorithms.

Magnesium-regulated oxygen vacancies of cobalt-nickel layered double hydroxide nanosheets for ultrahigh performance asymmetric supercapacitors.

Rational design of layered double hydroxide (LDH) electrodes is of great significance for high-performance supercapacitors (SCs). Herein, ultrathin cobalt-nickel-magnesium layered double hydroxide (CoNiMg-LDH) nanosheets with plentiful oxygen vacancies are synthesized via sacrificial magnesium-based replacement reaction at room temperature. Self-doping and mild reduction of magnesium can significantly increase the concentration of oxygen vacancies in CoNiMg-LDH, which promotes the electrochemical charge transfer efficiency and enhances the adsorption ability of electrolytes. Density functional theory (DFT) calculations also indicate that Mg2+ doping can decrease the formation energy of oxygen vacancies in CoNiMg-LDH nanosheets, which increases the concentration of oxygen vacancies. Thus, the assembled asymmetric supercapacitor CoNiMg-LDH//Actived Carbon accomplishes a superior capacity of âˆ¼ 333 C g-1 (208 F g-1) at 1 A g-1 and presents a gravimetric energy density of 73.9 Wh kg-1 at 0.8 kW kg-1. It presents only 13% capacity loss at 20 A g-1 after 5000 cycles. This discovery emphasizes the positive role of magnesium in regulating oxygen vacancies to improve the performance of supercapacitors, which should be beneficial for extending the scope of superior SCs active materials.

Early hepatoid adenocarcinoma of the stomach with signet ring cell carcinoma: A case report and clinicopathological features.

Background: Hepatoid adenocarcinoma of the stomach (HAS) is a rare subtype of gastric cancer with poor prognosis, and its clinicopathological features are not well understood, so the pathology from the clinical biopsy is easily misdiagnosed, especially for special or atypical HAS. We present an extremely rare early HAS with signet ring cell carcinoma and evaluate its clinicopathological features. Case presentation: A 51-year-old female patient of Chinese Han ethnicity with upper abdominal pain for 5 years and worsened abdominal pain for 1 month was admitted to our hospital. Esophagogastroduodenoscopy showed a submucosal tumor-like elevated lesion with central depression in the greater curvature of the junction between the antrum and body. Histopathological examination from the biopsy revealed medium-low-differentiation adenocarcinoma with signet ring cell carcinoma. Radical gastrectomy was performed, and the final diagnosis was early HAS with signet ring cell carcinoma. Conclusions: HAS with signet ring cell carcinoma is a special type of HAS and extremely rare. It is first presented for this extremely rare type of HAS, which contributes to strengthen the understanding for the clinicopathological characteristics of HAS and especially promote early detection of HAS.

Early verrucous cell carcinoma of the esophagus: a case report and endoscopic and histologic features.

BACKGROUND: Verrucous cell carcinoma of the esophagus (VCCE) is an extremely rare tumor and generally detected at advanced stage. Despite of its slow growth and well differentiation, it has very poor prognosis with high mortality. Therefore, early detection is a critical to improve patients' survival. However, no early cases of VCCE have been reported and the endoscopic features of early VCCE are not well described. We herein report the endoscopic and histologic features of an early VCCE. CASE PRESENTATION: A 54-year-old man with a history of excessive alcohol and tobacco use was admitted to our hospital because of chronic persistent swallowing dysfunction for six months. White light endoscopy revealed a flat lesion covered with scattered leukoplakia in the middle esophagus. Magnifying endoscopy with narrow-band imaging showed tiny irregular papillary microsurface structure. The lesion was considered as early esophageal cancer and completely resected with endoscopic submucosal dissection. Histological examination confirmed that the lesion was early VCCE which was limited within the mucosal lamina propria (m2). CONCLUSION: VCCE is rare with poor prognosis. This is a report of early VCCE and description of its endoscopic features which will contribute to early detection of these cancers.