A Deep Learning Model for Predicting Molecular Subtype of Breast Cancer by Fusing Multiple Sequences of DCE-MRI From Two Institutes.

RATIONALE AND OBJECTIVES: To evaluate the performance of deep learning (DL) in predicting different breast cancer molecular subtypes using DCE-MRI from two institutes. MATERIALS AND METHODS: This retrospective study included 366 breast cancer patients from two institutes, divided into training (n = 292), validation (n = 49) and testing (n = 25) sets. We first transformed the public DCE-MRI appearance to ours to alleviate small-data-size and class-imbalance issues. Second, we developed a multi-branch convolutional-neural-network (MBCNN) to perform molecular subtype prediction. Third, we assessed the MBCNN with different regions of interest (ROIs) and fusion strategies, and compared it to previous DL models. Area under the curve (AUC) and accuracy (ACC) were used to assess different models. Delong-test was used for the comparison of different groups. RESULTS: MBCNN achieved the optimal performance under intermediate fusion and ROI size of 80 pixels with appearance transformation. It outperformed CNN and convolutional long-short-term-memory (CLSTM) in predicting luminal B, HER2-enriched and TN subtypes, but without demonstrating statistical significance except against CNN in TN subtypes, with testing AUCs of 0.8182 vs. [0.7208, 0.7922] (p=0.44, 0.80), 0.8500 vs. [0.7300, 0.8200] (p=0.36, 0.70) and 0.8900 vs. [0.7600, 0.8300] (p=0.03, 0.63), respectively. When predicting luminal A, MBCNN outperformed CNN with AUCs of 0.8571 vs. 0.7619 (p=0.08) without achieving statistical significance, and is comparable to CLSTM. For four-subtype prediction, MBCNN achieved an ACC of 0.64, better than CNN and CLSTM models with ACCs of 0.48 and 0.52, respectively. CONCLUSION: Developed DL model with the feature extraction and fusion of DCE-MRI from two institutes enabled preoperative prediction of breast cancer molecular subtypes with high diagnostic performance.

Constraints on regional projections of mean and extreme precipitation under warming.

The projected changes in the hydrological cycle under global warming remain highly uncertain across current climate models. Here, we demonstrate that the observational past warming trend can be utilized to effectively co1nstrain future projections in mean and extreme precipitation on both global and regional scales. The physical basis for such constraints relies on the relatively constant climate sensitivity in individual models and the reasonable consistency of regional hydrological sensitivity among the models, which is dominated and regulated by the increases in atmospheric moisture. For the high-emission scenario, on the global average, the projected changes in mean precipitation are lowered from 6.9 to 5.2% and those in extreme precipitation from 24.5 to 18.1%, with the inter-model variances reduced by 31.0 and 22.7%, respectively. Moreover, the constraint can be applied to regions in middle-to-high latitudes, particularly over land. These constraints result in spatially resolved corrections that deviate substantially and inhomogeneously from the global mean corrections. This study provides regionally constrained hydrological responses over the globe, with direct implications for climate adaptation in specific areas.

Initial experience with radiomics of carotid perivascular adipose tissue in identifying symptomatic plaque.

Background: Carotid atherosclerotic ischemic stroke threatens human health and life. The aim of this study is to establish a radiomics model of perivascular adipose tissue (PVAT) around carotid plaque for evaluation of the association between Peri-carotid Adipose Tissue structural changes with stroke and transient ischemic attack. Methods: A total of 203 patients underwent head and neck computed tomography angiography examination in our hospital. All patients were divided into a symptomatic group (71 cases) and an asymptomatic group (132 cases) according to whether they had acute/subacute stroke or transient ischemic attack. The radiomic signature (RS) of carotid plaque PVAT was extracted, and the minimum redundancy maximum correlation, recursive feature elimination, and linear discriminant analysis algorithms were used for feature screening and dimensionality reduction. Results: It was found that the RS model achieved the best diagnostic performance in the Bagging Decision Tree algorithm, and the training set (AUC, 0.837; 95%CI: 0.775, 0.899), testing set (AUC, 0.834; 95%CI: 0.685, 0.982). Compared with the traditional feature model, the RS model significantly improved the diagnostic efficacy for identifying symptomatic plaques in the testing set (AUC: 0.834 vs. 0.593; Z = 2.114, p = 0.0345). Conclusion: The RS model of PVAT of carotid plaque can be used as an objective indicator to evaluate the risk of plaque and provide a basis for risk stratification of carotid atherosclerotic disease.

Relationship Analysis Between Pericoronary Fat Attenuation Index and Parameters of Single Plaque.

OBJECTIVE: The aim of the study is to investigate the relationship between plaque parameters and pericoronary fat attenuation index (FAI). METHODS: A retrospective collection was performed on 227 patients with coronary heart disease who underwent coronary computed tomography angiography examinations in our hospital from May 2021 to April 2023, with a total of 254 right coronary or left anterior descending coronary arteries exhibiting solitary plaques within the FAI measurement area. Based on whether the proximal coronary FAI value was ≥ -70.0 HU, patients and coronary arteries were divided into FAI-positive group (67 cases, 73 coronary arteries) and FAI-negative group (160 cases, 181 coronary arteries). Quantitative parameters of coronary solitary plaques were collected, including stenosis severity, plaque length, plaque volume, plaque composition ratios, minimal luminal area, and calcification score, as well as qualitative parameters such as plaque types and high-risk plaques. Differences in plaque parameters between the FAI-positive and FAI-negative groups were compared. RESULTS: The proportion of positive remodeling in the FAI-positive group (73 coronary arteries) was higher than that in the FAI-negative group (181 coronary arteries) with statistical significance (89.0% vs 78.5%, P = 0.049). Multivariate analysis revealed that positive remodeling was a risk factor for abnormal FAI values in solitary plaques (odds ratio, 2.271, P = 0.049). CONCLUSIONS: The FAI-positive group had a higher proportion of positive remodeling, and positive remodeling was an independent risk factor for positive FAI values.

Assessing the Role of Different Heterogeneous Regions in DCE-MRI for Predicting Molecular Subtypes of Breast Cancer based on Network Architecture Search and Vision Transformer.

Breast cancer, the most common female malignancy, is highly heterogeneous, manifesting as different molecular subtypes. It is clinically important to distinguish between these molecular subtypes due to marked differences in prognosis, treatment and survival outcomes. In this study, we first performed convex analysis of mixtures (CAM) analysis on both intratumoral and peritumoral regions in DCE-MRI to generate multiple heterogeneous regions. Then, we developed a vision transformer (ViT)-based DL model and performed network architecture search (NAS) to evaluate all the combination of different heterogeneous regions for predicting molecular subtypes of breast cancer. Experimental results showed that the input plasma from both peritumoral and intratumoral regions, and the fast-flow kinetics from intratumoral regions were critical for predicting different molecular subtypes, achieving an area under receiver operating characteristic curve (AUROC) value of 0.66-0.68.Clinical Relevance- This study reduces the redundancy in multiple heterogeneous subregions and supports the precise prediction of molecular subtypes, which is of potential importance for the medicine care and treatment planning of patients with breast cancer.

Storyline attribution of human influence on a record-breaking spatially compounding flood-heat event.

Attribution of compound events informs preparedness for emerging hazards with disproportionate impacts. However, the task remains challenging because space-time interactions among extremes and uncertain dynamic changes are not satisfactorily addressed in the well-established attribution framework. For attributing the 2020 record-breaking spatially compounding flood-heat event in China, we conduct a storyline attribution analysis by designing simulation experiments via a weather forecast model, quantifying component-based attributable changes, and comparing with historical flow analogs. We quantify that given the large-scale circulation, anthropogenic influence to date has exacerbated the extreme Mei-yu rainfall in the mid-lower reaches of the Yangtze River during June-July 2020 by ~6.5% and warmed the co-occurring seasonal extreme heat in South China by ~1°C. Our projections show a further intensification of the compound event by the end of this century, with moderate emissions making the rainfall totals ~14% larger and the season ~2.1°C warmer in South China than the 2020 status.

Cisplatin-induced oxPAPC release enhances MDSCs infiltration into LL2 tumour tissues through MCP-1/CCL2 and LTB4/LTB4R pathways.

Lung cancer is the leading global cause of cancer-related death, however, resistance to chemotherapy drugs remains a huge barrier to effective treatment. The elevated recruitment of myeloid derived suppressor cells (MDSCs) to tumour after chemotherapy has been linked to resistance of chemotherapy drugs. Nevertheless, the specific mechanism remains unclear. oxPAPC is a bioactive principal component of minimally modified low-density lipoproteins and regulates inflammatory response. In this work, we found that cisplatin, oxaliplatin and ADM all increased oxPAPC release in tumour. Treating macrophages with oxPAPC in vitro stimulated the secretion of MCP-1 and LTB4, which strongly induced monocytes and neutrophils chemotaxis, respectively. Injection of oxPAPC in vivo significantly upregulated the percentage of MDSCs in tumour microenvironment (TME) of wild-type LL2 tumour-bearing mice, but not CCL2-/- mice and LTB4R-/- mice. Critically, oxPAPC acted as a pro-tumor factor in LL2 tumour model. Indeed, cisplatin increased oxPAPC level in tumour tissues of WT mice, CCL2-/- and LTB4R-/- mice, but caused increased infiltration of Ly6Chigh monocytes and neutrophils only in WT LL2-bearing mice. Collectively, our work demonstrates cisplatin treatment induces an overproduction of oxPAPC and thus recruits MDSCs infiltration to promote the tumour growth through the MCP-1/CCL2 and LTB4/LTB4R pathways, which may restrict the effect of multiple chemotherapy. This provides evidence for a potential strategy to enhance the efficacy of multiple chemotherapeutic drugs in the treatment of lung cancer by targeting oxPAPC.

The Hadley circulation in the Pangea era.

The Pangea era is an exceptional phase in Earth's history. It is characterized by its hothouse climate state and the latest supercontinent. Thus, it is expected that atmospheric circulation in the Pangea era was largely different from that of the modern world. Here, we study the Hadley circulation in the Pangea era and compare it with that of the present, by performing climate simulations. Our results show that the annual mean Hadley cells are about 20% and 45% weaker than that in the pre-industrial (PI) climate, and their poleward edges are about 2° wider in latitude. The austral winter cell is weakened by 27% and expanded by 2.6°, while the changes of the boreal winter cell are not significant. One distinctive feature is that the ascending branches of the boreal and austral winter cells shift to 23°S and 18°N, respectively, which are much more poleward than their present locations. Our analyses demonstrate that the weakening and widening of the Hadley circulation is due to increasing tropical and subtropical static stability, and that the poleward shifts of the ascending branches of the winter cells are associated with the geographic configuration of the supercontinent Pangea.

Quantifying climate conditions for the formation of coals and evaporites.

Coals and evaporites are commonly used as qualitative indicators of wet and dry environments in deep-time climate studies, respectively. Here, we combine geological records with climate simulations to establish quantitative relationships of coals and evaporites with temperature and precipitation over the Phanerozoic. We show that coal records were associated with a median temperature of 25°C and precipitation of 1300 mm yr-1 before 250 Ma. Afterwards, coal records appeared with temperatures between 0°C and 21°C and precipitation of 900 mm yr-1. Evaporite records were associated with a median temperature of 27°C and precipitation of 800 mm yr-1. The most remarkable result is that net precipitation associated with coal and evaporite records remained constant across time. The results here have important implications for quantifying climate conditions for other lithologic indicators of climate and for predicting exogenetic ore deposits.

Continental drift shifts tropical rainfall by altering radiation and ocean heat transport.

Shifts in the position of the intertropical convergence zone (ITCZ) have great importance for weather, climate, and society. The ITCZ shifts have been extensively studied in current and future warmer climate; however, little is known for its migration in the past on geological time scales. Using an ensemble of climate simulations over the past 540 million years, we show that ITCZ migrations are controlled primarily by continental configuration through two competing pathways: hemispheric radiation asymmetry and cross-equatorial ocean heat transport. The hemispheric asymmetry of absorbed solar radiation is produced mainly by land-ocean albedo contrast, which can be predicted using only the landmass distribution. The cross-equatorial ocean heat transport is strongly associated with the hemispheric asymmetry of surface wind stress, which is, in turn, controlled by the hemispheric asymmetry of ocean surface area. These results allow the influence of continental evolution on global ocean-atmosphere circulations to be understood through simple mechanisms that depend primarily on the latitudinal distribution of land.

Circular RNA circFARSA promotes the tumorigenesis of non-small cell lung cancer by elevating B7H3 via sponging miR-15a-5p.

Non-small cell lung cancer (NSCLC) is currently one of the malignant tumors with the highest incidence and mortality rate in China. Circular RNA hsa_circ_0000896 (circFARSA) has been reported as being an oncogene and a potential biomarker for NSCL. However, the functional role and action mechanism of circFARSA in NSCLC progression have not been fully elucidated. The present study demonstrated that circFRASA was upregulated in NSCLC tissues and cell lines, and its expression was positively correlated with poor prognosis of patients with NSCLC. Further experiments revealed that circFARSA knockdown inhibited cell proliferation, migration, and invasion in vitro experiments, but overexpression of circFARSA exhibited opposite results. Mechanistically, circFARSA facilitated the malignant phenotype of NSCLC cells by enhancing B7H3 expression through sponging miR-15a-5p. In vivo experiments, knockdown of circFARSA restricted tumor growth and metastasis. In conclusion, circFARSA served as a sponge of miR-15a-5p to promote tumorigenesis and development of NSCLC by upregulation of B7H3 expression, which provided evidence of circFARSA maybe act as a novel therapeutic target for NSCLC.

Integrated strategy of network analysis prediction and experimental validation to elucidate the possible mechanism of compound Turkish gall ointment in treating eczema.

BACKGROUND: Compound Turkish gall ointment (CTGO) has a long history of being widely used as a folk medicine in Xinjiang for the treatment of eczema. CTGO is currently in the pre-investigational new drug application stage, but its pharmacological mechanisms of action have not yet been clarified. METHODS: First, a sensitive and reliable ultra-high performance liquid chromatography-Q exactive hybrid quadrupole-orbitrap high-resolution accurate mass spectrometry (UHPLC-Q-Orbitrap HRMS) technique was established. Second, an integrative strategy of network analysis and molecular docking based on identified and retrieved ingredients was implemented to investigate the potential targets and pathways involved in the treatment of eczema with CTGO. Finally, Sprague-Dawley (SD) rats with eczema were prepared to verify the predicted results. The skin conditions of the rats were observed, evaluated, and scored. Skin tissues were observed by hematoxylin-eosin (HE) staining, and the levels of serum interferon-γ (IFN-γ) and interleukin-4 (IL-4) were determined by enzyme-linked immunosorbent assay (ELISA). The expression levels of toll-like receptor 4 (TLR4), nuclear factor kappa-B p65 (NF-κB p65), interleukin-1ß (IL-1ß), and tumor necrosis factor-α (TNF-α) were detected by real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: A total of 29 compounds were identified. We found 38 active components and 58 targets for the treatment of eczema, which included 118 signaling pathways related to inflammation, immunity, and apoptosis. CTGO significantly improved the skin surface and histopathological characteristics of eczema-affected rats, downregulated the expression of IL-4, TLR4, NF-κB (p65), IL-1ß, and TNF-α, and upregulated the expression level of IFN-γ. CONCLUSION: We predicted and validated our prediction that CTGO may be used to treat eczema by affecting the TLR4/NF-κB signaling pathway, which provides guidance for future experimental studies.

A high-resolution climate simulation dataset for the past 540 million years.

The Phanerozoic Eon has witnessed considerable changes in the climate system as well as abundant animals and plant life. Therefore, the evolution of the climate system in this Eon is worthy of extensive research. Only by studying climate changes in the past can we understand the driving mechanisms for climate changes in the future and make reliable climate projections. Apart from observational paleoclimate proxy datasets, climate simulations provide an alternative approach to investigate past climate conditions of the Earth, especially for long time span in the deep past. Here we perform 55 snapshot simulations for the past 540 million years, with a 10-million-year interval, using the Community Earth System Model version 1.2.2 (CESM1.2.2). The climate simulation dataset includes global distributions of monthly surface temperatures and precipitation, with a 1° horizontal resolution of 0.9° × 1.25° in latitude and longitude. This open access climate dataset is useful for multidisciplinary research, such as paleoclimate, geology, geochemistry, and paleontology.

Methylene-bridge tryptophan fatty acylation regulates PI3K-AKT signaling and glucose uptake.

Protein fatty acylation regulates numerous cell signaling pathways. Polyunsaturated fatty acids (PUFAs) exert a plethora of physiological effects, including cell signaling regulation, with underlying mechanisms to be fully understood. Herein, we report that docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) regulate PI3K-AKT signaling by modifying PDK1 and AKT2. DHA-administered mice exhibit altered phosphorylation of proteins in signaling pathways. Methylene bridge-containing DHA/EPA acylate δ1 carbon of tryptophan 448/543 in PDK1 and tryptophan 414 in AKT2 via free radical pathway, recruit both the proteins to the cytoplasmic membrane, and activate PI3K signaling and glucose uptake in a tryptophan acylation-dependent but insulin-independent manner in cultured cells and in mice. DHA/EPA deplete cytosolic PDK1 and AKT2 and induce insulin resistance. Akt2 knockout in mice abrogates DHA/EPA-induced PI3K-AKT signaling. Our results identify PUFA's methylene bridge tryptophan acylation, a protein fatty acylation that regulates cell signaling and may underlie multifaceted effects of methylene-bridge-containing PUFAs.

Association between urinary polycyclic aromatic hydrocarbons metabolites and high-normal blood pressure in coke oven workers / 中国职业医学

@#Objective （ ） To investigate the association between urinary polycyclic aromatic hydrocarbons PAHs metabolites - Methods and high normal blood pressure in coke oven workers. A total of 433 coke oven workers were selected as the study - subjects using convenient sampling method. They were divided into normal blood pressure group and high normal blood pressure group according to their blood pressure level. The levels of ten kinds of urinary hydroxylated PAHs metabolites were measured by - Results - high performance liquid chromatography mass spectrometry. Among the subjects,57.5% had high normal blood - ， - ， - pressure. The levels of 1 hydroxynathalene 2 hydroxyphenanthrene 1 hydroxyphenanthrene and the metabolite of total PAHs - （ P ） in the high normal blood pressure group were higher than those in the normal blood pressure group all <0.05 . The results of - ， - ， - ， the multivariate logistic regression analysis showed that urinary 1 hydroxynathalene 2 hydroxyfluorene 3 hydroxychrysene - （ P ）， and metabolite of total PAHs were all risk factors for high normal blood pressure in coke oven workers all <0.05 after ， ， ， ， ， adjusting for confounding factors such as gender length of service body mass index smoking index alcohol consumption tea ， ， ， Conclusion consumption night shift exercise frequency and other PAHs metabolites. Exposure to PAHs in coke oven plants may increase the risk of elevated blood pressure within the normal range among coke oven workers.

Calcineurin inactivation inhibits pyruvate dehydrogenase complex activity and induces the Warburg effect.

Calcineurin is a calcium- and calmodulin-dependent serine/threonine protein phosphatase that connects the Ca2+-dependent signalling to multiple cellular responses. Calcineurin inhibitors (CNIs) have been widely used to suppress immune response in allograft patients. However, CNIs significantly increase cancer incidence in transplant recipients compared with the general population. Accumulating evidence suggests that CNIs may promote the malignant transformation of cancer cells in addition to its role in immunosuppression, but the underlying mechanisms remain poorly understood. Here, we show that calcineurin interacts with pyruvate dehydrogenase complex (PDC), a mitochondrial gatekeeper enzyme that connects two key metabolic pathways of cells, glycolysis and the tricarboxylic acid cycle. Mitochondrial-localized calcineurin dephosphorylates PDHA1 at Ser232, Ser293 and Ser300, and thus enhances PDC enzymatic activity, remodels cellular glycolysis and oxidative phosphorylation, and suppresses cancer cell proliferation. Hypoxia attenuates mitochondrial translocation of calcineurin to promote PDC inactivation. Moreover, CNIs promote metabolic remodelling and the Warburg effect by blocking calcineurin-mediated PDC activation in cancer cells. Our findings indicate that calcineurin is a critical regulator of mitochondrial metabolism and suggest that CNIs may promote tumorigenesis through inhibition of the calcineurin-PDC pathway.

Mitochondrial STAT5A promotes metabolic remodeling and the Warburg effect by inactivating the pyruvate dehydrogenase complex.

Signal transducer and activator 5a (STAT5A) is a classical transcription factor that plays pivotal roles in various biological processes, including tumor initiation and progression. A fraction of STAT5A is localized in the mitochondria, but the biological functions of mitochondrial STAT5A remain obscure. Here, we show that STAT5A interacts with pyruvate dehydrogenase complex (PDC), a mitochondrial gatekeeper enzyme connecting two key metabolic pathways, glycolysis and the tricarboxylic acid cycle. Mitochondrial STAT5A disrupts PDC integrity, thereby inhibiting PDC activity and remodeling cellular glycolysis and oxidative phosphorylation. Mitochondrial translocation of STAT5A is increased under hypoxic conditions. This strengthens the Warburg effect in cancer cells and promotes in vitro cell growth under hypoxia and in vivo tumor growth. Our findings indicate distinct pro-oncogenic roles of STAT5A in energy metabolism, which is different from its classical function as a transcription factor.

A human tissue map of 5-hydroxymethylcytosines exhibits tissue specificity through gene and enhancer modulation.

DNA 5-hydroxymethylcytosine (5hmC) modification is known to be associated with gene transcription and frequently used as a mark to investigate dynamic DNA methylation conversion during mammalian development and in human diseases. However, the lack of genome-wide 5hmC profiles in different human tissue types impedes drawing generalized conclusions about how 5hmC is implicated in transcription activity and tissue specificity. To meet this need, we describe the development of a 5hmC tissue map by characterizing the genomic distributions of 5hmC in 19 human tissues derived from ten organ systems. Subsequent sequencing results enabled the identification of genome-wide 5hmC distributions that uniquely separates samples by tissue type. Further comparison of the 5hmC profiles with transcriptomes and histone modifications revealed that 5hmC is preferentially enriched on tissue-specific gene bodies and enhancers. Taken together, the results provide an extensive 5hmC map across diverse human tissue types that suggests a potential role of 5hmC in tissue-specific development; as well as a resource to facilitate future studies of DNA demethylation in pathogenesis and the development of 5hmC as biomarkers.

The role of oxidized phospholipids in the development of disease.

Oxidized phospholipids (OxPLs), complex mixtures of phospholipid oxidation products generated during normal or pathological processes, are increasingly recognized to show bioactive effects on many cellular signalling pathways. There is a growing body of evidence showing that OxPLs play an important role in many diseases, so it is essential to define the specific role of OxPLs in different diseases for the design of disease therapies. In vastly diverse pathological processes, OxPLs act as pro-inflammatory agents and contribute to the progression of many diseases; in addition, they play a role in anti-inflammatory processes, promoting the dissipation of inflammation and inhibiting the progression of some diseases. In addition to participating in the regulation of inflammatory responses, OxPLs affect the occurrence and development of diseases through other pathways, such as apoptosis promotion. In this review, the different and even opposite effects of different OxPL molecular species are discussed. Furthermore, the specific effects of OxPLs in various diseases, as well as the receptor and cellular mechanisms involved, are summarized.