Sex disparities of clinical manifestations in acute pulmonary embolism and predictive value for in-hospital mortality: Insights from CURES.

BACKGROUND: Pulmonary embolism (PE) is a common and potentially fatal disease, with differences in mortality rates among PE patients of different sexes. This study aims to investigate the disparities in clinical manifestations and in-hospital mortality rates between sexes in PE patients, as well as the association of clinical symptoms with in-hospital mortality. METHODS: We analyzed data from the China pUlmonary thromboembolism REgistry Study (CURES), a nationwide, multicenter, prospective registry focusing on patients with acute PE. Using propensity score matching (PSM) to pair male and female patients with PE, we explored the correlation between clinical symptoms and in-hospital mortality through multivariable regression analysis. RESULTS: A total of 15,203 patients with acute PE were enrolled, and 380 died during hospitalization. The incidence of chest pain, hemoptysis, and palpitations was significantly higher in males compared to females. The incidence of dyspnea, fever, and syncope was higher in females. Hemoptysis and dyspnea were associated with increased in-hospital mortality in males, whereas dyspnea, fever, and palpitations were linked to higher mortality in females. Overall, males exhibited a higher in-hospital mortality than females (2.9 % vs. 2.1 %, p = 0.002). After matching 13,130 patients using the PSM method, the mortality rate of males remained higher than that of females (2.7 % vs. 2.1 %, p = 0.020). CONCLUSIONS: Our study demonstrates that male patients with PE have a higher risk of in-hospital mortality than females. Significant differences in clinical symptoms between sexes are associated with increased mortality risk, emphasizing the need for clinical awareness.

Risk factors for acute kidney injury and impact of earlier anticoagulation on renal function in patients with normotensive pulmonary embolism: a retrospective cohort study.

OBJECTIVE: We aimed to investigate the risk factors for acute kidney injury (AKI) after normotensive pulmonary embolism (PE) and the impact of anticoagulation on renal recovery. DESIGN: Multicentred, retrospective cohort study. SETTING: Data from four tertiary hospitals in China were captured. All available measurements of serum creatinine (SCr) during hospitalisation and follow-up were collected. PARTICIPANTS: Patients with acute PE and those without haemodynamic instability were enrolled. All recruited patients were followed up for up to 2 years. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was the occurrence of AKI, defined by the Kidney Disease Improving Global Outcomes criteria. The secondary outcome was the recovery of renal function. The time interval between PE onset and the initiation of anticoagulation was analysed to obtain its influence on the recovery of renal function. RESULTS: A total of 461 patients with acute normotensive PE were enrolled. A transient elevation of SCr during hospitalisation was observed. The incidence of AKI among normotensive patients was 18.9%. Brain natriuretic peptide (BNP) NT-proBNP elevation (adjusted HR (aHR) 2.27, 95% CI 1.33 to 3.86) and history of chronic kidney disease (aHR 4.81, 95% CI 2.44 to 9.48) were associated with the development of AKI during hospitalisation. Earlier initiation of anticoagulation therapy (within 5 days after PE onset, compared with over 6 days) promoted an early recovery of renal function (adjusted OR 0.26, 95% CI 0.08 to 0.84, p=0.025). CONCLUSIONS: Renal impairment and AKI were highly prevalent among patients with normotensive patients. The occurrence of AKI was associated with right heart function. Patients who developed AKI after PE would benefit from earlier anticoagulation therapy for an early recovery of renal function.

Convergence and divergence in neurostructural signatures of unipolar and bipolar depressions: Insights from surface-based morphometry and prospective follow-up.

BACKGROUND: Bipolar disorder (BD) is often misidentified as unipolar depression (UD) during its early stages, typically until the onset of the first manic episode. This study aimed to explore both shared and unique neurostructural changes in patients who transitioned from UD to BD during follow-up, as compared to those with UD. METHODS: This study utilized high-resolution structural magnetic resonance imaging (MRI) to collect brain data from individuals initially diagnosed with UD. During the average 3-year follow-up, 24 of the UD patients converted to BD (cBD). For comparison, the study included 48 demographically matched UD patients who did not convert and 48 healthy controls. The MRI data underwent preprocessing using FreeSurfer, followed by surface-based morphometry (SBM) analysis to identify cortical thickness (CT), surface area (SA), and cortical volume (CV) among groups. RESULTS: The SBM analysis identified shared neurostructural characteristics between the cBD and UD groups, specifically thinner CT in the right precentral cortex compared to controls. Unique to the cBD group, there was a greater SA in the right inferior parietal cortex compared to the UD group. Furthermore, no significant correlations were observed between cortical morphological measures and cognitive performance and clinical features in the cBD and UD groups. LIMITATIONS: The sample size is relatively small. CONCLUSIONS: Our findings suggest that while cBD and UD exhibit some common alterations in cortical macrostructure, numerous distinct differences are also present. These differences offer valuable insights into the neuropathological underpinnings that distinguish these two conditions.

Sex- and age-associated factors drive the pathophysiology of MASLD.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly associated with obesity. Sex and age affect MASLD prevalence and pathophysiology. The use of animal models fed Western-style diets is vital for investigating the molecular mechanisms contributing to metabolic dysregulation and for facilitating novel drug target identification. However, the sex-associated and age-associated mechanisms underlying the pathophysiology remain poorly understood. This knowledge gap limits the development of personalized sex-specific and age-specific drug treatments. METHODS: Young (7 wk) and aged (52 wk) male and female mice were fed a high-fat diet (HFD) or low-fat diet. Liver metabolome (>600 molecules) and transcriptome profiles were analyzed. RESULTS: Male and female mice fed an HFD developed obesity, glucose intolerance, and hepatic steatosis. However, fasting blood glucose, insulin, and serum alanine aminotransferase levels were higher in males fed an HFD, indicating a more severe metabolic disease. In addition, males showed significant increases in liver diacylglycerides and glycosylceramides (known mediators of insulin resistance and fibrosis), and more changes in the transcriptome: extracellular matrix organization and proinflammatory genes were elevated only in males. In contrast, no major increase in damaging lipid classes was observed in females fed an HFD. However, aging affected the liver to a greater extent in females. Acylcarnitine levels were significantly reduced, suggestive of changes in fatty acid oxidation, and broad changes in the transcriptome were observed, including reduced oxidative stress response gene expression and alterations in lipid partitioning genes. CONCLUSIONS: Here, we show distinct responses to an HFD between males and females. Our study underscores the need for using both sexes in drug target identification studies, and characterizing the molecular mechanisms contributing to the MASLD pathophysiology in aging animals.

Electroacupuncture improves cognitive impairment after ischemic stroke based on regulation of mitochondrial dynamics through SIRT1/PGC-1α pathway.

In recent years, the mechanism of acupuncture in the treatment of post-stroke cognitive impairment (PSCI) has not been fully elucidated. The balance between mitochondrial fission and fusion is important for PSCI. Our previous research demonstrated that electroacupuncture can improve learning and memory in middle cerebral artery ischemia reperfusion (MCAO/R) rats. However, the specific mechanism by which electroacupuncture improves learning and memory in MCAO/R rats by regulating mitochondrial fission and fusion needs to be further investigated. The MCAO/R rats was developed using the line-bolt method. The rats were randomly divided into sham-operated (Sham), model (MCAO/R), electroacupuncture (MCAO/R + EA) and sham-electroacupuncture (MCAO/R + sham EA) groups. Investigating the effects of EA on the expression of Sirtuin1 (SIRT1), peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), Optic atrophy 1R + (OPA1) and Dynamin-related protein 1 (DRP1) in hippocampal neurons and on the morphology and function of hippocampal neurons and mitochondria. EA was able to reduce neurologic deficit scores and cerebral infarct volume and improve new object discrimination in MCAO/R rats, but there were no significant changes in these indices in the sham-electroacupuncture group. Moreover, EA increased the expression of SIRT1, PGC-1α, and OPA1 in hippocampal tissues, inhibited the expression of DRP1, attenuated neuronal and mitochondrial damage, and reduced mitochondrial fragmentation. The mechanism by which EA improves learning memory deficits in MCAO/R rats may be related to the inhibition of SIRT1/PGC-1α expression, the enhancement of mitochondrial fusion and the obstruction of its fission, and the reduction of hippocampal neuronal damage.

Engineering S-scheme mCN@mPDIP molecular heterojunction with highly efficient interface charge transfer for photocatalytic aerobic oxidation synthesis.

The construction of S-scheme heterojunctions, which offers a promising approach for spatially separating photogenerated charge carriers with high redox potentials and multimolecular activation, represents a viable modification strategy in photocatalytic applications. However, the prevalent insufficient contact areas between two components result in low interface charge transfer efficiency, thereby impeding the photocatalytic performance of such heterostructures. Herein, we address this limitation by introducing a unique mCN@mPDIP molecular heterojunction through a pH-triggered molecule self-assembly eutectoid technique, enabling intimate interface contact and promoting highly efficient interfacial charge transfer following an S-scheme mechanism. Consequently, the mCN@mPDIP molecular heterojunction achieves significantly improved charge separation efficiency and higher concentration of active carriers compared to typical bCN-bPDIP bulk heterojunction and nCN/nPDIP nano heterojunction. Combined with the effective sulfide activation on mPDIP sites and O2 activation on mCN sites, the resulting mCN@mPDIP demonstrates outstanding activity in the photocatalytic aerobic oxidation of sulfides into sulfoxides without any redox mediators.

Nonreciprocal routing of microwave photons with broad bandwidth via magnon-cavity chiral coupling.

We propose a scheme for realizing nonreciprocal microwave photon routing with two cascaded magnon-cavity coupled systems, which work around the exceptional points of a parity-time (PT)-symmetric Hamiltonian. An almost perfect nonreciprocal transmission can be achieved with a broad bandwidth, where the transmission for a forward-propagating photon can be flexibly controlled with the backpropagating photon being isolated. The transmission or isolated direction can be reversed via simply controlling the magnetic field direction applied to the magnons. The isolation bandwidth is improved by almost three times in comparison with the device based on a single PT-symmetric system. Moreover, the effect of intrinsic cavity loss and added thermal noises is considered, confirming the experimental feasibility of the nonreciprocal device and potential applications in quantum information processing.

Huangtu decoction alleviates chronic diarrhea of spleen-yang deficiency in mice by altering host metabolome and intestinal microbiota composition.

BACKGROUND: Huangtu decoction (HTD), a traditional Chinese medicine recipe, warms the spleen, nourishes the blood, and stops bleeding. It has been used to treat dysentery, gastrointestinal bleeding, diarrhea, and other symptoms caused by spleen-yang deficiency for more than 2,000 years in China. However, the mechanism underlying the treatment of chronic diarrhea due to spleen-yang deficiency (CDSD) using HTD remains unclear. AIMS: This study investigated whether HTD could mediate intestinal flora and serum metabolites to improve CDSD symptoms using a mouse model. METHODS: A CDSD mouse model induced by senna and an abnormal diet was constructed. The regulatory effects of HTD at 12.5, 25.0, and 50.0 g/kg/d on CDSD mice were assessed by measuring their bodyweight, diarrhea rate, loose stool rate, and histopathology. Changes in the intestinal flora of CDSD mice were analyzed by 16S rRNA gene sequencing. Untargeted serum metabolomic analysis was performed using ultra-high performance liquid chromatography-mass spectrometry/mass spectrometry (UHPLC-MS/MS). RESULTS: HTD had a modulating effect on CDSD by reducing the weight loss, diarrhea rate, loose stool rate, and pathologic damage. Intestinal flora analysis showed that HTD altered the community composition by decreasing the abundance of Allobaculum, Lactobacillus, and Ruminococcus. Serum metabolomics revealed that ascorbate and aldarate metabolism, aldosterone synthesis and secretion, platelet activation, hypoxia-inducible factor 1 signaling pathway, inositol phosphate metabolism, phosphatidylinositol signaling, galactose metabolism, and alpha-linolenic acid metabolism were modulated after HTD treatment. CONCLUSION: HTD may alleviate CDSD symptoms by reducing weight loss, diarrhea rate, loose stool rate, and pathologic damage caused by modeling and regulating intestinal flora and serum metabolites in CDSD mice.

Association of C-reactive protein/albumin ratio with mortality in patients with Traumatic Brain Injury: A systematic review and meta-analysis.

Objective: This study examines the C-reactive protein (CRP)/albumin ratio (CAR) as an inflammation-based prognostic score for predicting mortality in patients with Traumatic Brain Injury (TBI). Methods: We systematically searched the electronic databases PubMed, Embase, and Cochrane up to February 2024. Our inclusion criteria encompassed studies investigating CAR-predicted mortality in patients with TBI. We calculated the Odds Ratio (OR) and associated 95 % confidence intervals (95 % CI) using a random-effects model. Quality assessment of the included studies was appraised using a Newcastle-Ottawa scale. Results: A total of five studies comprising 1040 patients were included in this meta-analysis. The pooled results indicated that CAR was associated with mortality in patients with TBI (OR = 1.88, 95 % CI: 1.05-3.36, P < 0.0001). The findings of subgroup analysis indicated that the relationship between CAR and mortality in patients with TBI did not vary with the severity of the condition. Conclusions: CAR emerges as a valuable prognostic tool for mortality in patients with TBI, underscoring its potential role in early risk stratification and management strategies.

Targeting Ovarian Cancer Stem Cells by Dual Inhibition of the Long Noncoding RNA HOTAIR and Lysine Methyltransferase EZH2.

Persistence of cancer stem cells (CSCs) is believed to contribute to resistance to platinum-based chemotherapy and disease relapse in ovarian cancer, the fifth leading cause of cancer-related death among US women. HOXC transcript antisense RNA (HOTAIR) is a long noncoding RNA (lncRNA) overexpressed in high-grade serous ovarian cancer and linked to chemoresistance. However, HOTAIR impacts chromatin dynamics in ovarian CSCs and how this oncogenic lncRNA contributes to drug resistant disease are incompletely understood. Here we generated HOTAIR knock-out (KO) high-grade serous ovarian cancer cell lines using paired CRISPR guide RNA design to investigate the function of HOTAIR. We show loss of HOTAIR function re-sensitized ovarian cancer cells to platinum treatment and decreased the population of ovarian CSCs. Furthermore, HOTAIR KO inhibited development of stemness-related phenotypes, including spheroid formation ability, as well as expression of key stemness-associated genes ALDH1A1, NOTCH3, SOX9, and PROM1. HOTAIR KO altered both the cellular transcriptome and chromatin accessibility landscape of multiple oncogenic-associated genes and pathways, including the NF-kB pathway. HOTAIR functions as an oncogene by recruiting enhancer of zeste 2 (EZH2) to catalyze H3K27 tri-methylation to suppress downstream tumor suppressor genes, and it was of interest to inhibit both HOTAIR and EZH2. In vivo, combining a HOTAIR inhibitor with an EZH2 inhibitor and platinum chemotherapy decreased tumor formation and increased survival. These results suggest a key role for HOTAIR in ovarian CSCs and malignant potential. Targeting HOTAIR in combination with epigenetic therapies may represents therapeutic strategy to ameliorate ovarian cancer progression and resistance to platinum-based chemotherapy.

An experimental study on the curing of desert sand using bio-cement.

In order to promote the development and utilization of desert sand, this study is based on researching the most suitable ratio of bio-cement, analyzing the shear strength and permeability of improved desert sand by combining bio-cement and fly ash, and clarifying the applicability of tap water in bio-cement. The relationship between the two and the microstructural properties was investigated using the results of the straight shear test and the permeability test. The results showed that the urease solution prepared with tap water had a more pronounced temperature resistance. The urea concentration and the corresponding pH environment had a direct effect on the urease activity. The calcium carbonate yield was positively correlated with the calcium concentration, and the urea concentration was higher in the ranges of 1.0-1.5 mol/L. As the enzyme-to-gel ratio decreased, the calcium carbonate precipitate produced per unit volume of urease solution gradually converged to a certain value. The shear strength (increased by 37.9%) and permeability (decreased by about 8.9-68.5%) of the modified desert sand peaked with the increase in fly ash content. The microscopic test results indicated that the fly ash could provide nucleation sites for the bio-cement, effectively improving the mechanical properties of the desert sand. The crystal types of calcium carbonate in the modified desert sand were calcite and aragonite, which were the most stable crystal types. This study provides innovative ideas for interdisciplinary research in the fields of bioengineering, ecology and civil engineering.

Sustainable versatile chitin aerogels: facile synthesis, structural control and high-efficiency acoustic absorption.

Bio-based materials with excellent acoustic absorption properties are in great demand in architecture, interior, and human settlement applications for efficient noise control. In this study, crayfish shells, a form of kitchen waste, are utilized as the primary material to produce ultralight and multifunctional chitin aerogels, which effectively eliminate noise. Different replacement solvents and freezing rates were employed to regulate the porous structures of chitin aerogels, and their resulting acoustic absorption performance was investigated. Results demonstrate that employing deionized water as the replacement solvent and utilizing a common-freeze mode (frozen via refrigerator at -26 °C) can produce chitin aerogels with larger porosity (96.26%) and apertures, as well as thicker pore walls. This results in superior broadband acoustic absorption performance (with a maximum absorption coefficient reaching 0.99) and higher Young's modulus (28 kPa). Conversely, chitin aerogels solvent-exchanged with tert-butyl alcohol or subjected to quick-freeze mode (frozen via liquid nitrogen) exhibit smaller porosity (92.32% and 94.84%) and apertures, thereby possessing stronger diffuse reflection of visible light (average reflectance of 94.30% and 88.18%), and enhanced low-frequency (500 to 1600 Hz) acoustic absorption properties. Additionally, the acoustic absorption mechanism of fabricated chitin aerogels was predicted using a simple three-parameter analysis Johnson-Champoux-Allard-Lafarge (JCAL) model. This study presents a novel approach to developing multifunctional biomass materials with excellent acoustic absorption properties, which could have a wide range of potential applications.

Damage regularity and multifractal analysis of sol-gel reflection coating of KDP crystal under low UV irradiation flux.

This study employed multifractal analysis to investigate the changes in surface morphology of SiO2 anti-reflective coatings prepared on KDP substrates using the sol-gel method, under various conditions of ultraviolet (UV) irradiance. The coatings were successfully fabricated, and the chemical structure of the SiO2 sol was comprehensively characterized using Solid-State Nuclear Magnetic Resonance (SSNMR) technology. Under low UV irradiance (4 J/cm2), repeated experiments revealed a crack-induced mechanism of surface fatigue damage. Utilizing Scanning Electron Microscopy (SEM), the study discovered the induction effect of initial crack defects in UV-damaged coatings and established a damage model. Furthermore, Atomic Force Microscopy (AFM) was used to acquire images of the coatings' surface morphology at different damage levels, which were analyzed using the multifractal spectrum f(α). This analysis confirmed the multifractal nature of the coatings both before and after damage. This study identified significant effects of UV irradiation on the width of the multifractal spectrum and Δf, indicating that the SiO2 anti-reflective coatings exhibit multifractal characteristics under various damage states. The coatings displayed a pattern of decreasing and then increasing singularity spectrum width, height distribution unevenness, and surface roughness with increasing damage. This study demonstrates that multifractal analysis is an effective tool for describing the complexity of the surface morphology of sol-gel-derived anti-reflective coatings for the first time and for validating their multifractal properties across different stages of UV damage. HIGHLIGHTS: Damage dynamic process of KDP crystal sol-gel coating was described by SEM&AFM; The crack propagation mechanism of sol-gel coating under UV radiation is proposed; The damage evolution of sol-gel coating was described by multifractal analysis.

Notopterygium Incisum Extract Promotes Apoptosis by Preventing the Degradation of BIM in Colorectal Cancer.

OBJECTIVE: Colorectal cancer (CRC), a prevalent malignancy worldwide, has prompted extensive research into anticancer drugs. Traditional Chinese medicinal materials offer promising avenues for cancer management due to their diverse pharmacological activities. This study investigated the effects of Notopterygium incisum, a traditional Chinese medicine named Qianghuo (QH), on CRC cells and the underlying mechanism. METHODS: The sulforhodamine B assay and colony formation assay were employed to assess the effect of QH extract on the proliferation of CRC cell lines HCT116 and Caco-2. Propidium iodide (PI) staining was utilized to detect cell cycle progression, and PE Annexin V staining to detect apoptosis. Western blotting was conducted to examine the levels of apoptotic proteins, including B-cell lymphoma 2-interacting mediator of cell death (BIM), B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (BAX) and cleaved caspase-3, as well as BIM stability after treatment with the protein synthesis inhibitor cycloheximide. The expression of BAX was suppressed using lentivirus-mediated shRNA to validate the involvement of the BIM/BAX axis in QH-induced apoptosis. The in vivo effects of QH extract on tumor growth were observed using a xenograft model. Lastly, APCMin+ mice were used to study the effects of QH extract on primary intestinal tumors. RESULTS: QH extract exhibited significant in vitro anti-CRC activities evidenced by the inhibition of cell proliferation, perturbation of cell cycle progression, and induction of apoptosis. Mechanistically, QH extract significantly increased the stability of BIM proteins, which undergo rapid degradation under unstressed conditions. Knockdown of BAX, the downstream effector of BIM, significantly rescued QH-induced apoptosis. Furthermore, the in vitro effect of QH extract was recapitulated in vivo. QH extract significantly inhibited the tumor growth of HCT116 xenografts in nude mice and decreased the number of intestinal polyps in the APCMin+ mice. CONCLUSION: QH extract promotes the apoptosis of CRC cells by preventing the degradation of BIM.

Experimental study on the mechanical properties of desert sand improved by the combination of additives and bio-cement.

Bio-cement is a green and energy-saving building material that has attracted much attention in the field of ecological environment and geotechnical engineering in recent years. The aim of this study is to investigate the use of bio-cement (enzyme-induced calcium carbonate precipitation-EICP) in combination with admixtures for the improvement of desert sands, which can effectively improve the mechanical properties of desert sands and is particularly suitable for sand-rich countries. In addition, the suitability of tap water in bio-cement was elucidated and the optimum ratio of each influencing factor when tap water is used as a solvent was derived. The results showed that peak values of unconfined compressive strength (maximum increase of about 130 times), shear strength (increase of 27.09%), calcium carbonate precipitation value (increase of about 4.39 times), and permeability (decrease of about 93.72 times) were obtained in the specimens modified by EICP combined with admixture as compared to the specimens modified by EICP only. The incorporation of skimmed milk powder, though significantly increasing the strength, is not conducive to cost control. The microscopic tests show that the incorporation of admixtures can provide nucleation sites for EICP, thus improving the properties of desert sand. This work can provide new research ideas for cross-fertilization between the disciplines of bio-engineering, ecology, and civil engineering.

Cardiomyocyte LGR6 alleviates ferroptosis in diabetic cardiomyopathy via regulating mitochondrial biogenesis.

AIMS: The majority of people with diabetes are susceptible to cardiac dysfunction and heart failure, and conventional drug therapy cannot correct the progression of diabetic cardiomyopathy. We assessed the potential role and therapeutic value of LGR6 (G protein-coupled receptor containing leucine-rich repeats 6) in diabetic cardiomyopathy. METHODS AND RESULTS: Type 2 diabetes models were established using high-fat diet/streptozotocin-induced diabetes in mice. LGR6 knockout mice were generated. Recombinant adeno-associated virus serotype 9 carrying LGR6 under the cardiac troponin T promoter was injected into diabetic mice. Cardiomyocytes incubated with high glucose (HG) were used to imitate diabetic cardiomyopathy in vitro. The molecular mechanism was explored through RNA sequencing and a chromatin immunoprecipitation assay. We found that LGR6 expression was upregulated in diabetic hearts and HL1 cardiomyocytes treated with HG. The LGR6 knockout aggravated, but cardiomyocyte-specific LGR6 overexpression ameliorated, cardiac dysfunction and remodeling in diabetic mice. Mechanistically, in vivo and in vitro experiments revealed that LGR6 deletion aggravated, whereas LGR6 overexpression alleviated, ferroptosis and disrupted mitochondrial biogenesis by regulating STAT3/Pgc1a signaling. STAT3 inhibition and Pgc1a activation abrogated LGR6 knockout-induced mitochondrial dysfunction and ferroptosis in diabetic mice. In addition, LGR6 activation by recombinant RSPO3 treatment ameliorated cardiac dysfunction, ferroptosis and mitochondrial dysfunction in diabetic mice. CONCLUSIONS: We identified a previously undescribed signaling pathway of the LGR6-STAT3-Pgc1a axis that plays a critical role in ferroptosis and mitochondrial disorders during diabetic cardiomyopathy and provides an option for treatment of diabetic hearts.

Integrated single-cell and bulk RNA sequencing revealed an epigenetic signature predicts prognosis and tumor microenvironment colorectal cancer heterogeneity.

BACKGROUND: Colorectal cancer (CRC) prognosis prediction is currently a major challenge. Epigenetic regulation has been widely reported for its role in cancer development. AIM: To construct a robust prognostic signature, we used developed and validated across datasets. METHODS: After constructing the signature, the prognostic value of the signature was evaluated in the TCGA cohort and six independent datasets (GSE17526, GSE17537, GSE33113, GSE37892, GSE39048 and GSE39582). The clinical, genomic and transcriptomic features related to the signature were identified. The correlations of the signature score with immune cell infiltration and cell-cell interactions were analyzed. The correlations between the signature score and the sensitivity to different drugs were also predicted. RESULTS: In the TCGA cohort, patients in the low-risk group according to the signature score had longer survival than those in the high-risk group, and this finding was validated in the validation datasets. The signature was a prognostic factor independent of age and sex and was correlated with stage and PD-1/PD-L1 expression. Area under the receiving operating characteristic curve was 0.72. Genomic association analyses revealed that samples from high-risk patients exhibited chromosomal instability. Transcriptomic analyses revealed that the signature score was significantly associated with multiple cellular pathways. Bulk RNA-seq and single-cell sequencing data revealed that the signature reflected differences in infiltrating immune cell-tumor cell interactions, especially for macrophages. The signature also predicted the putative drug sensitivity of CRC samples. CONCLUSION: The signature is a valuable biomarker for predicting CRC prognosis and reflects multiple features of CRC, especially macrophage infiltration in the microenvironment.

Alkynyl nicotinamides show antileukemic activity in drug-resistant acute myeloid leukemia.

Activating mutations of FLT3 contribute to deregulated hematopoietic stem and progenitor cell (HSC/Ps) growth and survival in patients with acute myeloid leukemia (AML), leading to poor overall survival. AML patients treated with investigational drugs targeting mutant FLT3, including Quizartinib and Crenolanib, develop resistance to these drugs. Development of resistance is largely due to acquisition of cooccurring mutations and activation of additional survival pathways, as well as emergence of additional FLT3 mutations. Despite the high prevalence of FLT3 mutations and their clinical significance in AML, there are few targeted therapeutic options available. We have identified 2 novel nicotinamide-based FLT3 inhibitors (HSN608 and HSN748) that target FLT3 mutations at subnanomolar concentrations and are potently effective against drug-resistant secondary mutations of FLT3. These compounds show antileukemic activity against FLT3ITD in drug-resistant AML, relapsed/refractory AML, and in AML bearing a combination of epigenetic mutations of TET2 along with FLT3ITD. We demonstrate that HSN748 outperformed the FDA-approved FLT3 inhibitor Gilteritinib in terms of inhibitory activity against FLT3ITD in vivo.

EDIL3/Del-1 prevents aortic dissection through enhancing internalization and degradation of apoptotic vascular smooth muscle cells.

Thoracic aortic dissection (TAD) is a severe disease, characterized by numerous apoptotic vascular smooth muscle cells (VSMCs). EDIL3/Del-1 is a secreted protein involved in macrophage efferocytosis in acute inflammation. Here, we aimed to investigate whether EDIL3 promoted the internalization and degradation of apoptotic VSMCs during TAD. The levels of EDIL3 were decreased in the serum and aortic tissue from TAD mice. Global edil3 knockout (edil3-/-) mice and edil3-/- bone marrow chimeric mice exhibited a considerable exacerbation in ß-aminopropionitrile monofumarate (BAPN)-induced TAD, accompanied with increased apoptotic VSMCs accumulating in the damaged aortic tissue. Two types of phagocytes, RAW264.7 cells and bone marrow-derived macrophages (BMDMs) were used for in vitro efferocytosis assay. edil3-deficient phagocytes exhibited inefficient internalization and degradation of apoptotic VSMCs. Instead, EDIL3 promoted the internalization phase through interacting with phosphatidylserine (PtdSer) on apoptotic VSMCs and binding to the macrophage ITGAV/αv-ITGB3/ß3 integrin. In addition, EDIL3 accelerated the degradation phase through activating LC3-associated phagocytosis (LAP). Mechanically, following the engulfment, EDIL3 enhanced the activity of SMPD1/acid sphingomyelinase in the phagosome through blocking ITGAV-ITGB3 integrin, which facilitates phagosomal reactive oxygen species (ROS) production by NAPDH oxidase CYBB/NOX2. Furthermore, exogenous EDIL3 supplementation alleviated BAPN-induced TAD and promoted apoptotic cell clearance. EDIL3 may be a novel factor for the prevention and treatment of TAD.Abbreviations: BAPN: ß-aminopropionitrile monofumarate; BMDM: bone marrow-derived macrophage; C12FDG: 5-dodecanoylaminofluorescein-di-ß-D-galactopyranoside; CTRL: control; CYBB/NOX2: cytochrome b-245, beta polypeptide; DCFH-DA: 2',7'-dichlorofluorescin diacetate; EDIL3/Del-1: EGF-like repeats and discoidin I-like domains 3; EdU: 5-ethynyl-2'-deoxyuridine; EVG: elastic van Gieson; H&E: hematoxylin and eosin; IL: interleukin; LAP: LC3-associated phagocytosis; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; NAC: N-acetylcysteine; PtdSer: phosphatidylserine; rEDIL3: recombinant EDIL3; ROS: reactive oxygen species; SMPD1: sphingomyelin phosphodiesterase 1; TAD: thoracic aortic dissection; TEM: transmission electron microscopy; VSMC: vascular smooth muscle cell; WT: wild-type.