Warfarin-related nephropathy: unveiling the hidden dangers of anticoagulation.

Warfarin-related nephropathy (WRN) is defined as acute kidney injury subsequent to excessive anticoagulation with warfarin. Patients with mechanical prosthetic valves require long-term anticoagulant therapy. Nonetheless, warfarin remains the sole available option for anticoagulant therapy. Consequently, patients with mechanical prosthetic valves constitute a special group among the entire anticoagulant population. The present study recorded two cases of patients who had undergone mechanical prosthetic valve surgery and were receiving warfarin therapy. They presented to the hospital with gross hematuria and progressive creatinine levels. Notably, their international normalized ratio (INR) did not exceed three. Subsequent renal biopsies confirmed WRN with IgA nephropathy. The two patients continued to receive warfarin as anticoagulation therapy and were prescribed oral corticosteroids and cyclophosphamide, which resulted in improved renal function during the follow-up. Based on a review of all relevant literature and the present study, we proposed a new challenge: must elevated INR levels be one of the criteria for clinical diagnosis of WRN? Perhaps some inspiration can be drawn from the present article.

Intracavity generation of glioma stem cell-specific CAR macrophages primes locoregional immunity for postoperative glioblastoma therapy.

Glioblastoma multiforme (GBM) remains incurable despite aggressive implementation of multimodal treatments after surgical debulking. Almost all patients with GBM relapse within a narrow margin around the initial resected lesion due to postsurgery residual glioma stem cells (GSCs). Tracking and eradicating postsurgery residual GSCs is critical for preventing postoperative relapse of this devastating disease, yet effective strategies remain elusive. Here, we report a cavity-injectable nanoporter-hydrogel superstructure that creates GSC-specific chimeric antigen receptor (CAR) macrophages/microglia (MΦs) surrounding the cavity to prevent GBM relapse. Specifically, we demonstrate that the CAR gene-laden nanoporter in the hydrogel can introduce GSC-targeted CAR genes into MΦ nuclei after intracavity delivery to generate CAR-MΦs in mouse models of GBM. These CAR-MΦs were able to seek and engulf GSCs and clear residual GSCs by stimulating an adaptive antitumor immune response in the tumor microenvironment and prevented postoperative glioma relapse by inducing long-term antitumor immunity in mice. In an orthotopic patient-derived glioblastoma humanized mouse model, the combined treatment with nanoporter-hydrogel superstructure and CD47 antibody increased the frequency of positive immune responding cells and suppressed the negative immune regulating cells, conferring a robust tumoricidal immunity surrounding the postsurgical cavity and inhibiting postoperative glioblastoma relapse. Therefore, our work establishes a locoregional treatment strategy for priming cancer stem cell-specific tumoricidal immunity with broad application in patients suffering from recurrent malignancies.

A Prognostic Model Based on mRNA Expression Analysis of Esophageal Squamous Cell Carcinoma.

Background: The aim of this study was to identify prognostic markers for esophageal squamous cell carcinoma (ESCC) and build an effective prognostic nomogram for ESCC. Methods: A total of 365 patients with ESCC from three medical centers were divided into four cohorts. In the discovery phase of the study, we analyzed transcriptional data from 179 cancer tissue samples and identified nine marker genes using edgeR and rbsurv packages. In the training phase, penalized Cox regression was used to select the best marker genes and clinical characteristics in the 179 samples. In the verification phase, these marker genes and clinical characteristics were verified by internal validation cohort (n = 58) and two external cohorts (n = 81, n = 105). Results: We constructed and verified a nomogram model based on multiple clinicopathologic characteristics and gene expression of a patient cohort undergoing esophagectomy and adjuvant radiochemotherapy. The predictive accuracy for 4-year overall survival (OS) indicated by the C-index was 0.75 (95% CI, 0.72-0.78), which was statistically significantly higher than that of the American Joint Committee on Cancer (AJCC) seventh edition (0.65). Furthermore, we found two marker genes (TM9SF1, PDZK1IP) directly related to the OS of esophageal cancer. Conclusion: The nomogram presented in this study can accurately and impersonally predict the prognosis of ESCC patients after partial resection of the esophagus. More research is required to determine whether it can be applied to other patient populations. Moreover, we found two marker genes directly related to the prognosis of ESCC, which will provide a basis for future research.

Inhaled mRNA Nanoformulation with Biogenic Ribosomal Protein Reverses Established Pulmonary Fibrosis in a Bleomycin-Induced Murine Model.

Idiopathic pulmonary fibrosis (IPF), a lethal respiratory disease with few treatment options, occurs due to repetitive microinjuries to alveolar epithelial cells (AECs) and progresses with an overwhelming deposition of extracellular matrix (ECM), ultimately resulting in fibrotic scars and destroyed the alveolar architecture. Here, an inhaled ribosomal protein-based mRNA nanoformulation is reported for clearing the intrapulmonary ECM and re-epithelializing the disrupted alveolar epithelium, thereby reversing established fibrotic foci in IPF. The nanoformulation is sequentially assembled by a ribosomal protein-condensed mRNA core, a bifunctional peptide-modified corona and keratinocyte growth factor (KGF) with a PEGylated shielding shell. When inhaled via a nebulizer, the nanoformulations carried by microdrops are deposited in the alveoli, and penetrate into fibrotic foci, where the outer KGFs are detached after matrix metalloproteinase 2 (MMP2) triggering. The RGD motif-grafted cores then expose and specifically target the integrin-elevated cells for the intracellular delivery of mRNA. Notably, repeated inhalation of the nanoformulations accelerates the clearance of locoregional collagen by boosting the intralesional expression of MMP13 and alveolar re-epithelialization mediated by KGFs, which synergistically ameliorates the lung function of a bleomycin-induced murine model. Therefore, this work provides an alternative mRNA-inhalation delivery strategy, which shows great potential for the treatment of IPF.

The association between atrial fibrillation and in-hospital outcomes in chronic kidney disease patients with acute coronary syndrome: findings from the improving care for cardiovascular disease in China-acute coronary syndrome (CCC-ACS) project.

BACKGROUND: Atrial fibrillation (AF) is the most common cardiac arrhythmia in patients with chronic kidney disease (CKD) and acute coronary syndrome (ACS). This study aimed to explore the frequency and impact of AF on clinical outcomes in CKD patients with ACS. METHODS: CKD inpatients with ACS between November 2014 and December 2018 were included based on the improving care for cardiovascular disease in China-ACS (CCC-ACS) project. Included patients were divided into an AF group and a non-AF group according to the discharge diagnosis. Multivariable logistic regression was used to adjust for potential confounders. RESULTS: A total of 16,533 CKD patients with ACS were included. A total of 1418 (8.6%) patients had clinically recognized AF during hospitalization, 654 of whom had an eGFR of 45 to < 60 ml/min/1.73 m2, and 764 had an estimated glomerular filtration rate (eGFR) < 45 ml/min/1.73 m2. Compared with the non-AF group, the AF group had a higher risk of in-hospital mortality [OR 1.250; 95% CI (1.001-1.560), P = 0.049] and major adverse cardiovascular events (MACEs) [OR 1.361; 95% CI (1.197-1.547), P < 0.001]. We also found that compared with patients with eGFR 45 to < 60 ml/min/1.73 m2, patients with eGFR < 45 ml/min/1.73 m2 had a 1.512-fold increased risk of mortality and a 1.435-fold increased risk of MACEs. CONCLUSIONS: AF was a risk factor affecting the short-term prognosis of ACS patients in the CKD population. Furthermore, the lower the eGFR, the higher the risk of in-hospital mortality and MACEs in CKD patients with ACS. TRIAL REGISTRY: Clinicaltrial.gov, NCT02306616. Registered 29 November 2014, https://clinicaltrials.gov/ct2/show/NCT02306616?term=NCT02306616&draw=2&rank=1.

Application of natural products derivatization method in the design of targeted anticancer agents from 2000 to 2018.

A concept, natural products derivatization method (NPDM), was introduced to assess the influence of natural products on the discovery of targeted anticancer agents. Subsequently, 106 new molecular entities (NMEs) for targeted anticancer agents from 2000 to 2018 were categorized and sorted into four types: ND (Natural Product Derivative), SND (Synthetic Natural Derived), B (Biological Macromolecule), S (Totally synthetic in origin). Furthermore, by setting molecular targeted agents (MTA), cellular targeted agents (CTA), vascular targeted agents (VTA) and immuno targeted agents (ITA) as study subject, ND category and SND category were reviewed from aspects including natural products source, action mechanism and their share in all NMEs in order to comprehensively evaluate the significance of NPDM in the design and development of targeted anticancer agents, and the prospects of this method was also put forward.

Synthesis and Activity Investigation of Novel 1H-Purin-6(9H)-one and 3H-Imidazo[4,5-d][1,2,3]triazin-4(7H)-one Derivatives.

Novel 1H-purin-6(9H)-one (D) and 3H-imidazo[4,5-d][1,2,3]trazin-4(7H)-one (E) derivatives were designed, synthesized, and characterized by 1H NMR, 13C NMR and high-resolution mass spectrometry spectra. Their herbicidal activity bioassay showed that compound 7d exhibited relatively good activity with 70.4% inhibition rate against Amaranthus retroflexus in postemergence treatments at 1500 g/ha. Antitumor activity indicated that most of the title compounds displayed potent antitumor activity at 20 µM, among all of the promising compounds possessing lower IC50 values than that of temozolomide, compound 7i demonstrated highest activity inhibiting both HepG-2 and U-118 MG cell lines with IC50 values of 2.0 and 3.8 µM, respectively. The structure-activity relationship analysis revealed that introduction of halogen atoms, a bulky bridging bond between benzene ring and nitrogen atom, longer R2 substituents could contribute to the improvement of antitumor activity. Analysis suggested that compound 7i might have potential as new highly active antitumor agent. Overall, D series had better anticancer activities than E series derivatives.