Renal cell carcinoma (RCC) is a kidney cancer that is originated from the lined proximal convoluted tubule, and its major histological subtype is clear cell RCC (ccRCC). This study aimed to ...retrospectively analyze single-cell RNA sequencing (scRNA-seq) data from the Gene Expression Omnibus (GEO) database, to explore the correlation among the evolution of tumor microenvironment (TME), clinical outcomes, and potential immunotherapeutic responses in combination with bulk RNA-seq data from The Cancer Genome Atlas (TCGA) database, and to construct a differentiation-related genes (DRG)-based prognostic risk signature (PRS) and a nomogram to predict the prognosis of ccRCC patients. First, scRNA-seq data of ccRCC samples were systematically analyzed, and three subsets with distinct differentiation trajectories were identified. Then, ccRCC samples from TCGA database were divided into four DRG-based molecular subtypes, and it was revealed that the molecular subtypes were significantly correlated with prognosis, clinicopathological features, TME, and the expression levels of immune checkpoint genes (ICGs). A DRG-based PRS was constructed, and it was an independent prognostic factor, which could well predict the prognosis of ccRCC patients. Finally, we constructed a prognostic nomogram based on the PRS and clinicopathological characteristics, which exhibited a high accuracy and a robust predictive performance. This study highlighted the significance of trajectory differentiation of ccRCC cells and TME evolution in predicting clinical outcomes and potential immunotherapeutic responses of ccRCC patients, and the nomogram provided an intuitive and accurate method for predicting the prognosis of such patients.
Colorectal carcinoma (CRC) is the second most deadly cancer worldwide. Therapies that take advantage of DNA repair defects have been explored in various tumors but not yet systematically in CRC. ...Here, we found that Diphosphoinositol Pentakisphosphate Kinase 2 (PPIP5K2), an inositol pyrophosphate kinase, was highly expressed in CRC and associated with a poor prognosis of CRC patients. In vitro and in vivo functional studies demonstrated that PPIP5K2 could promote the proliferation and migration ability of CRC cells independent of its inositol pyrophosphate kinase activity. Mechanically, S1006 dephosphorylation of PPIP5K2 could accelerate its dissociation with 14-3-3 in the cytoplasm, resulting in more nuclear distribution. Moreover, DNA damage treatments such as doxorubicin (DOX) or irradiation (IR) could induce nuclear translocation of PPIP5K2, which subsequently promoted homologous recombination (HR) repair by binding and recruiting RPA70 to the DNA damage site as a novel scaffold protein. Importantly, we verified that S1006 dephosphorylation of PPIP5K2 could significantly enhance the DNA repair ability of CRC cells through a series of DNA repair phenotype assays. In conclusion, PPIP5K2 is critical for enhancing the survival of CRC cells via facilitating DNA HR repair. Our findings revealed an unrecognized biological function and mechanism model of PPIP5K2 dependent on S1006 phosphorylation and provided a potential therapeutic target for CRC patients.
Mutations in the gene encoding the bone morphogenetic protein receptor type II (BMPR2) are the commonest genetic cause of pulmonary arterial hypertension (PAH). However, the effect of BMPR2 mutations ...on clinical phenotype and outcomes remains uncertain.
We analysed individual participant data of 1550 patients with idiopathic, heritable, and anorexigen-associated PAH from eight cohorts that had been systematically tested for BMPR2 mutations. The primary outcome was the composite of death or lung transplantation. All-cause mortality was the secondary outcome. Hazard ratios (HRs) for death or transplantation and all-cause mortality associated with the presence of BMPR2 mutation were calculated using Cox proportional hazards models stratified by cohort.
Overall, 448 (29%) of 1550 patients had a BMPR2 mutation. Mutation carriers were younger at diagnosis (mean age 35·4 SD 14·8 vs 42·0 17·8 years), had a higher mean pulmonary artery pressure (60·5 13·8 vs 56·4 15·3 mm Hg) and pulmonary vascular resistance (16·6 8·3 vs 12·9 8·3 Wood units), and lower cardiac index (2·11 0·69 vs 2·51 0·92 L/min per m2; all p<0·0001). Patients with BMPR2 mutations were less likely to respond to acute vasodilator testing (3% 10 of 380 vs 16% 147 of 907; p<0·0001). Among the 1164 individuals with available survival data, age-adjusted and sex-adjusted HRs comparing BMPR2 mutation carriers with non-carriers were 1·42 (95% CI 1·15–1·75; p=0·0011) for the composite of death or lung transplantation and 1·27 (1·00–1·60; p=0·046) for all-cause mortality. These HRs were attenuated after adjustment for potential mediators including pulmonary vascular resistance, cardiac index, and vasoreactivity. HRs for death or transplantation and all-cause mortality associated with BMPR2 mutation were similar in men and women, but higher in patients with a younger age at diagnosis (p=0·0030 for death or transplantation, p=0·011 for all-cause mortality).
Patients with PAH and BMPR2 mutations present at a younger age with more severe disease, and are at increased risk of death, and death or transplantation, compared with those without BMPR2 mutations.
Cambridge NIHR Biomedical Research Centre, Medical Research Council, British Heart Foundation, Assistance Publique-Hôpitaux de Paris, INSERM, Université Paris-Sud, Intermountain Research and Medical Foundation, Vanderbilt University, National Center for Advancing Translational Sciences, National Institutes of Health, National Natural Science Foundation of China, and Beijing Natural Science Foundation.
We sought to investigate the characteristics, survival and risk factors for mortality in Chinese patients with connective tissue disease (CTD)-associated pulmonary arterial hypertension (APAH) in ...modern therapy era. 129 consecutive adult patients who visited one of three referral centres in China with a diagnosis of CTD-APAH confirmed by right heart catheterisation during the previous 5 years were enrolled. The end-point was all-cause death or data censoring. Systemic lupus erythematosus was the most common underlying CTD (49%) and systemic sclerosis just accounted for 6% in this cohort. The overall survival at 1 and 3 years was 92% and 80%, respectively. Pericardial effusion, a shorter 6-min walk distance, lower mixed venous oxygen saturation, higher pulmonary vascular resistance (PVR) and alkaline phosphatase (ALP), and lower total cholesterol levels were all associated with a higher risk of death among the study population. Higher PVR and ALP were independent predictors of mortality. In conclusion, unlike in western patients, systemic lupus erythematosus is the most common underlying disease in Chinese patients with CTD-APAH. The survival of Chinese patients with CTD-APAH in the modern treatment era is similar to that in western countries. Elevated PVR and ALP are independent risk factors for poor outcomes.
Direct oral anticoagulants (DOACs) are widely used for secondary prevention of venous thromboembolism (VTE) but their clinical efficacy and safety are not established in Antiphospholipid Syndrome ...(APS) patients. There is only one randomized controlled trial published while others are still ongoing. Many non-randomized studies have been published in this field with conflicting opinions.
We conducted a systematic review using MEDLINE, EMBASE and Cochrane databases from 2000 until March 2018 regarding APS patients treated with DOACs. We performed a patient-level data meta-analysis to a) estimate the prevalence of recurrent thrombosis in APS patients treated with DOACs in the literature, and b) identify variables associated with recurrent thrombosis.
We identified 47 studies corresponding to 447 APS patients treated with DOACs. Three commercially available DOACs were analyzed: rivaroxaban (n = 290), dabigatran etexilate (n = 144) and apixaban (n = 13). A total of 73 out of 447 patients (16%) experienced a recurrent thrombosis while on DOACs with a mean duration until thrombosis of 12.5 months. Rates of recurrent thromboses were 16.9% and 15% in APS patients receiving either anti-Xa inhibitors or dabigatran respectively. Triple positivity (positivity for all three antiphospholipid antibodies) was associated with a four-fold increased risk of recurrent thrombosis (56% vs 23%; OR = 4.3 95%CI; 2.3–7.7, p < 0.0001) as well as a higher number of clinical criteria for APS classification. In patients treated with anti-Xa inhibitors, history of arterial thrombosis was associated with a higher risk of recurrent thrombosis (32% vs 14%; OR = 2.8 95%CI; 1.4–5.7, p = 0.006).
In conclusion, DOACs are not effective in all APS patients and should not be used routinely in these patients. Randomized controlled trials assessing clinical efficacy and safety as primary endpoints are underway. In the meantime, a registry of APS patients on DOACs could be proposed to establish in which APS subgroups DOACs would be a safe alternative to warfarin.
•Direct oral anticoagulants are not effective and safe in all APS patients.•Triple positive patients have a four-fold increased risk of recurrent thrombosis.•Most recurrent thromboses occur within 12 months after DOACs initiation.
Objective/Background
Proliferation is a widely recognized trigger for pulmonary hypertension (PH), a life‐threatening, progressive disorder of pulmonary blood vessels. This study was aimed to ...identify some proliferation associated genes/targets for better comprehension of PH pathogenesis.
Methods
Human pulmonary arterial smooth muscle cells (hPASMCs) were cultured in the presence or absence of human recombinant platelet derived growth factor (rhPDGF)‐BB. Cells were collected for metabolomics or transcriptomics study. Gene profiling of lungs of PH rats after hypoxia exposure or of PH patients were retrieved from GEO database.
Results
90 metabolites (VIP score >1, fold change >2 or <0.5 and p < .05) and 2701 unique metabolism associated genes (MAGs) were identified in rhPDGF‐BB treated hPASMCs compared to control cells. In addition, 1151 differentially expressed genes (313 upregulated and 838 downregulated) were identified in rhPDGF‐BB treated hPASMCs compared to control cells (fold change >2 or <0.5 and p < .05). 152 differentially expressed MAGs were then determined, out of which 9 hub genes (IL6, CXCL8, CCL2, CXCR4, CCND1, PLAUR, PLAU, HBEGF and F3) were defined as core proliferation associated hub genes in protein proten interaction analysis. In addition, the hub gene‐based LASSO model can predict the occurrence of PH (AUC = 0.88). The expression of CXCR4, as one of the hub genes, was positively correlated to immune cell infiltrates.
Conclusion
Our findings revealed some key proliferation associated genes in PH, which provide the crucial information concerning complex metabolic reprogramming and inflammatory modulation in response to proliferation signals and might offer therapeutic gains for PH.
Proliferation associated hub genes in pulmonary arterial smooth muscle cells (PASMCs) in response to platelet derived growth factor‐BB (PDGF‐BB) were explored by virtue of transcriptomics and metabolomics. Those hub genes might be responsible for proliferating PASMCs phenotype and associated with immune cell infiltrates into the lung tissues, contributing to the development of pulmonary vascular remodeling (created with BioRender.com).
Allylation and propargylation are two powerful synthetic strategies for making new substances that have been of significant importance in chemistry, medicine, and material fields. Conventional ...tactics employ various preformed allylation and propargylation reagents. In this study, a conceptually novel copper-catalyzed and B2pin2-mediated Umpolung reactivity of propargylic carbonates has been achieved for the first time, realizing both allylation and propargylation of aldehydes and ketones without additional reductants. Three types of allylation products and one type of propargylation product are generated efficiently, and all allylation products are formed with syn-configurations predominantly. The choice of ligands plays a vital role in modulating the Umpolung modes. The synthetic applications have been demonstrated in a myriad of further transformations including natural product synthesis, and systematic mechanistic studies have been conducted to reveal detailed insights into the Umpolung processes.
Deep learning-based super-resolution (SR) algorithms aim to reconstruct low-resolution (LR) images into high-fidelity high-resolution (HR) images by learning the low- and high-frequency information. ...Experts’ diagnostic requirements are fulfilled in medical application scenarios through the high-quality reconstruction of LR digital medical images.
Medical image SR algorithms should satisfy the requirements of arbitrary resolution and high efficiency in applications. However, there is currently no relevant study available. Several SR research on natural images have accomplished the reconstruction of resolutions without limitations. However, these methodologies provide challenges in meeting medical applications due to the large scale of the model, which significantly limits efficiency. Hence, we suggest a highly effective method for reconstructing medical images at any desired resolution.
Statistical features of medical images exhibit greater continuity in the region of neighboring pixels than natural images. Hence, the process of reconstructing medical images is comparatively less challenging. Utilizing this property, we develop a neighborhood evaluator to represent the continuity of the neighborhood while controlling the network’s depth.
The suggested method has superior performance across seven scales of reconstruction, as evidenced by experiments conducted on panoramic radiographs and two external public datasets. Furthermore, the proposed network significantly decreases the parameter count by over 20× and the computational workload by over 10× compared to prior researches. On large-scale reconstruction, the inference speed can be enhanced by over 5×.
The novel proposed SR strategy for medical images performs efficient reconstruction at arbitrary resolution, marking a significant breakthrough in the field. The given scheme facilitates the implementation of SR in mobile medical platforms.
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•A model for super-resolution of medical images with arbitrary resolution is present.•The proposed efficient method can increase the inference speed by five times.•The strategy provides a technical solution for deployment on mobile platforms.
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