Proteolytic activation of angiomotin by DDI2 promotes angiogenesis.

The scaffolding protein angiomotin (AMOT) is indispensable for vertebrate embryonic angiogenesis. Here, we report that AMOT undergoes cleavage in the presence of lysophosphatidic acid (LPA), a lipid growth factor also involved in angiogenesis. AMOT cleavage is mediated by aspartic protease DNA damage-inducible 1 homolog 2 (DDI2), and the process is tightly regulated by a signaling axis including neurofibromin 2 (NF2), tankyrase 1/2 (TNKS1/2), and RING finger protein 146 (RNF146), which induce AMOT membrane localization, poly ADP ribosylation, and ubiquitination, respectively. In both zebrafish and mice, the genetic inactivation of AMOT cleavage regulators leads to defective angiogenesis, and the phenotype is rescued by the overexpression of AMOT-CT, a C-terminal AMOT cleavage product. In either physiological or pathological angiogenesis, AMOT-CT is required for vascular expansion, whereas uncleavable AMOT represses this process. Thus, our work uncovers a signaling pathway that regulates angiogenesis by modulating a cleavage-dependent activation of AMOT.

Trichinella spiralis -induced immunomodulation signatures on gut microbiota and metabolic pathways in mice.

The hygiene hypothesis proposes that decreased exposure to infectious agents in developed countries may contribute to the development of allergic and autoimmune diseases. Trichinella spiralis, a parasitic roundworm, causes trichinellosis, also known as trichinosis, in humans. T. spiralis had many hosts, and almost any mammal could become infected. Adult worms lived in the small intestine, while the larvae lived in muscle cells of the same mammal. T. spiralis was a significant public health threat because it could cause severe illness and even death in humans who eat undercooked or raw meat containing the parasite. The complex interactions between gastrointestinal helminths, gut microbiota, and the host immune system present a challenge for researchers. Two groups of mice were infected with T. spiralis vs uninfected control, and the experiment was conducted over 60 days. The 16S rRNA gene sequences and untargeted LC/MS-based metabolomics of fecal and serum samples, respectively, from different stages of development of the Trichinella spiralis-mouse model, were examined in this study. Gut microbiota alterations and metabolic activity accompanied by parasite-induced immunomodulation were detected. The inflammation parameters of the duodenum (villus/crypt ratio, goblet cell number and size, and histological score) were involved in active inflammation and oxidative metabolite profiles. These profiles included increased biosynthesis of phenylalanine, tyrosine, and tryptophan while decreasing cholesterol metabolism and primary and secondary bile acid biosynthesis. These disrupted metabolisms adapted to infection stress during the enteral and parenteral phases and then return to homeostasis during the encapsulated phase. There was a shift from an abundance of Bacteroides in the parenteral phase to an abundance of probiotic Lactobacillus and Treg-associated-Clostridia in the encapsulated phase. Th2 immune response (IL-4/IL-5/IL-13), lamina propria Treg, and immune hyporesponsiveness metabolic pathways (decreased tropane, piperidine and pyridine alkaloid biosynthesis and biosynthesis of alkaloids derived from ornithine, lysine, and nicotinic acid) were all altered. These findings enhanced our understanding of gut microbiota and metabolic profiles of Trichinella -infected mice, which could be a driving force in parasite-shaping immune system maintenance.

Natural variation in WHITE-CORE RATE 1 regulates redox homeostasis in rice endosperm to affect grain quality.

Grain chalkiness reduces the quality of rice (Oryza sativa) and is a highly undesirable trait for breeding and marketing. However, the underlying molecular cause of chalkiness remains largely unknown. Here, we cloned the F-box gene WHITE-CORE RATE 1 (WCR1), which negatively regulates grain chalkiness and improves grain quality in rice. A functional A/G variation in the promoter region of WCR1 generates the alleles WCR1A and WCR1G, which originated from tropical japonica and wild rice Oryza rufipogon, respectively. OsDOF17 is a transcriptional activator that binds to the AAAAG cis-element in the WCR1A promoter. WCR1 positively affects the transcription of the metallothionein gene MT2b and interacts with MT2b to inhibit its 26S proteasome-mediated degradation, leading to decreased reactive oxygen species production and delayed programmed cell death in rice endosperm. This, in turn, leads to reduced chalkiness. Our findings uncover a molecular mechanism underlying rice chalkiness and identify the promising natural variant WCR1A, with application potential for rice breeding.

Radiotherapy-Driven Nanoprobes Targeting for Visualizing Tumor Infiltration Dynamics and Inducing Ferroptosis in Myeloid-Derived Suppressor Cells.

Myeloid-derived suppressor cells (MDSCs) significantly hinder the immune response to tumor radiotherapy (RT) because of their massive accumulation in tumors after RT, resulting in immunosuppression and poor clinical prognosis. Herein, we developed an anti-PD-L1 antibody-conjugated iron oxide nanoprobe (Fe3O4-αPD-L1) to target and induce ferroptosis in MDSCs, thereby alleviating RT resistance. Overexpression of PD-L1 in MDSCs following RT enables noninvasive in vivo magnetic resonance and positron emission tomography imaging using 89Zr-labeled nanoprobes to track the movement of MDSCs and their infiltration into the tumor. After uptake by MDSCs that infiltrated the tumor, Fe3O4-αPD-L1 nanoprobes were mainly found within the lysosome and triggered the Fenton reaction, resulting in the generation of abundant reactive oxygen species. This process leads to ferroptosis of MDSCs, characterized by lipid peroxidation and mitochondrial dysfunction, and effectively reprograms the immunosuppressive environment within the tumor following RT. This study highlights a strategy for monitoring and regulating the fate of MDSCs to alleviate RT resistance and ultimately achieve improved treatment outcomes.

Prussian Blue-Assisted NIR Triggered In-Situ Polymerized Nanocomposite Hydrogel for Wound Repair.

Hydrogels are commonly used as wound dressings to help maintain a moist environment around the wound and isolate contaminants, thus promoting healing. For irregular wounds, the slow healing process and even infection may occur due to the inability of dressings to adhere well to the wound. Prussian blue (PB) is a metal-organic framework (MOF) material with excellent photothermal conversion and superior stability. In this paper, a kind of near-infrared (NIR) light triggered in-situ polymerized antimicrobial hydrogel was prepared. The free radical initiator was encapsulated in the hollow PB by a phase change material (PCM) to maintain stability. The raised temperature triggered by NIR induced the release and decomposition of the initiator. The matrix was formed by the cross-linking of double bonds on modified chitosan. The quaternary amine groups of modified chitosan and the photothermal properties of PB enhanced the antimicrobial properties of the hydrogel. High-quality wound healing was demonstrated in the whole skin defect model. This study provides a new reference for the preparation of in-situ polymerized hydrogel dressings for irregular wounds.

Infants Born at Late Preterm Gestation: Management during the Birth Hospitalization.

OBJECTIVE: To examine the admission practices, frequency of common clinical morbidities, and rates of medical intervention in infants born at 34-36 weeks gestational age (GA, late preterm). STUDY DESIGN: This retrospective, single institution, cohort study analyzed electronic health records of infants born late preterm from 2019 through 2021. Infants with known congenital anomalies necessitating neonatal intensive care unit admission were excluded. Analysis included descriptive and inferential statistics. RESULTS: The study included 1022 infants: 209 (21%) 34 weeks GA, 263 (26%) 35 weeks GA, and 550 (54%) 36 weeks GA. Sixty-three percent of infants at 35 weeks GA and 78% of infants of 36 weeks GA remained in well newborn care throughout the birth hospitalization; infants born at 34 weeks GA were ineligible for well newborn care. The need for respiratory support was 32%, 18%, and 11% in infants of 34, 35, and 36 weeks GA, respectively. Supplemental tube feeds were administered in 55%, 24%, and 8% of infants of 34, 35, and 36 weeks GA, respectively. Most infants born at 34 weeks GA (91%) were placed in an incubator; this was less frequent in infants at 35 (37%) and 36 weeks (16%). Tachypnea, hypoglycemia, and hypothermia were noted in 40%, 61%, and 57% of infants, respectively. A subset of these infants (30% with tachypnea, 23% with hypoglycemia, and 46% with hypothermia) required medical intervention for these abnormalities. CONCLUSIONS: This single-center study provides an outlook on the care of infants born late preterm. Multicenter studies can contextualize these findings in order to develop clinical benchmarks and quality markers for this large population of infants.

Light environment affects the efficiency of surgical suture training.

BACKGROUND: Suture knotting is the basis of surgical skills. In the process of surgical skills learning, the surrounding environment, especially the light, will affect the efficiency of learning. This study investigated the effect of optical environment on the learning of stitching and knotting skills. METHODS: A total of 44 medical students were randomly divided into four groups and participated in the study of suture knotting in four different optical environments. During the process, we assess objective pressure level by testing salivary amylase activity Likert scale and objective structured clinical examination (OSCE) was used to estimate the subjective psychological state and overall skill mastery in surgical suturing respectively. RESULTS: Under high illumination conditions (700 lx), the salivary amylase activity of the high color temperature group (6000 K) was significantly higher than that of the low color temperature group (4000 K) (p < 0.0001). Similarly, under low illumination (300 lx), the salivary amylase activity of the high color temperature group was also significantly higher than that of the low color temperature group (p < 0.05). The student under high illumination conditions (700 lx) and the low color temperature (6000 K) have an autonomy score between 37-45, which is significantly higher compared to the other three groups (p < 0.0001). Group 2 has an average OSCE score of 95.09, which were significantly higher than those of the other three groups (p < 0.05). CONCLUSION: High illumination combined with low color temperature is considered as the optimal training conditions, promoting trainees' optimism, reducing stress levels, and enhancing learning efficiency. These results highlight the pivotal role of light environment in improving the quality and efficiency of surgical skills training.

Lithium Pre-Storage Enables High Initial Coulombic Efficiency and Stable Lithium-Enriched Silicon/Graphite Anode.

Application of silicon-based anodes is significantly challenged by low initial Coulombic efficiency (ICE) and poor cyclability. Traditional pre-lithiation reagents often pose safety concerns due to their unstable chemical nature. Achieving a balance between water-stability and high ICE in prelithiated silicon is a critical issue. Here, we present a lithium-enriched silicon/graphite material with an ultra-high ICE of ≥110 % through a high-stable lithium pre-storage methodology. Lithium pre-storage prepared a nano-drilled graphite material with surficial lithium functional groups, which can form chemical bonds with adjacent silicon during high-temperature sintering. This results in an unexpected O-Li-Si interaction, leading to in situ pre-lithiation of silicon nanoparticles and providing high stability in air and water. Additionally, the lithium-enriched silicon/graphite materials impart a combination of high ICE, high specific capacity (620 mAh g-1), and long cycling stability (>400 cycles). This study opens up a promising avenue for highly air- and water-stable silicon anode prelithiation methods.

The Role of ESRP1 in the Regulation of PHGDH in Estrogen Receptor-Positive Breast Cancer.

Resistance to hormone therapy leads to a recurrence of estrogen receptor-positive breast cancer. We have demonstrated that the epithelial splicing regulatory protein 1 (ESRP1) significantly affects cell/tumor growth and metabolism and is associated with a poor prognosis in this breast cancer subtype. In this study, we aimed to investigate the ESRP1 protein-messenger RNA (mRNA) interaction in hormone therapy-resistant breast cancer. RNA-binding protein immunoprecipitation (RIP) followed by Clariom D (Applied Biosystems/Thermo Fisher Scientific) transcriptomics microarray (RIP-Chip) was performed to identify mRNA-binding partners of ESRP1. The integration of RIP-Chip and immunoprecipitation-mass spectrometry analyses identified phosphoglycerate dehydrogenase (PHGDH), a key metabolic enzyme, as a binding partner of ESRP1 in hormone-resistant breast cancer. Bioinformatic analysis showed ESRP1 binding to the 5' untranslated region of PHGDH. RNA electrophoresis mobility shift assay and RIP-quantitative reverse transcription-polymerase chain reaction further validated the ESRP1-PHGDH binding. In addition, knockdown of ESRP1 decreased PHGDH mRNA stability significantly, suggesting the posttranscriptional regulation of PHGDH by ESRP1. The presence or absence of ESRP1 levels significantly affected the stability in tamoxifen-resistant LCC2 and fulvestrant-resistant LCC9 cells. PHGDH knockdown in tamoxifen-resistant cells further reduced the oxygen consumption rate (ranging from P = .005 and P = .02), mimicking the effects of ESRP1 knockdown. Glycolytic parameters were also altered (ranging P = .001 and P = .005). ESRP1 levels did not affect the stability of PHGDH in T-47D cells, although knockdown of PHGDH affected the growth of these cells. In conclusion, to our knowledge, this study, for the first time, reports that ESRP1 binds to the 5' untranslated region of PHGDH, increasing its mRNA stability in hormone therapy-resistant estrogen receptor-positive breast cancer. These findings provide evidence for a novel mechanism of action of RNA-binding proteins such as ESRP1. These new insights could assist in developing novel strategies for the treatment of hormone therapy-resistant breast cancer.

Is Toxoplasma gondii infection a concern in individuals with rheumatic diseases? Evidence from a case-control study based on serological diagnosis.

Toxoplasma gondii infection in clinical cases of rheumatic diseases is increasing, whereas, the relationship between T. gondii infection and rheumatic diseases is still ambiguous and contradictory. Thus, the present case-control study based on serological diagnosis was carried out to identify the underlying relationship between T. gondii infection and rheumatic diseases in China. Serological results showed that rheumatic patients (17.25%, 79/458) had a significantly higher T. gondii seroprevalence than control subjects (10.70%, 49/458) (p = 0.004). However, the difference in T. gondii seroprevalence among clinical rheumatic disease forms was insignificant. Moreover, disease duration not effect the T. gondii seroprevalence in the included clinical rheumatic patients. Three risk factors (presence of cats at home, blood transfusion history, and consumption of raw shellfish) were identified through multivariate analysis to affect the T. gondii seroprevalence in the included clinical rheumatic patients. In conclusion, these results indicate that the latent T. gondii infection in clinical rheumatic patients should cause alarm and attention in the course of future scientific research or clinical treatment.

Visible-Light Photoredox-Catalyzed Three-Component Reaction of Carbazoles with Alkenes and S-(Difluoromethyl)sulfonium Salt: A Practical Approach to Access Difluoroalkyl-Functionalized Carbazoles.

A mild and elegant multicomponent protocol for construction of CF2H-containing carbazoles was accomplished by visible-light photoredox catalysis with formation of two new C-C bonds in a single step to deliver a wide variety of structurally diverse difluoroalkylated carbazoles in moderate to good yields, featuring mild reaction conditions, synthetic simplicity, broad substrates, and good functional group tolerance.

Visible-light photoredox-catalyzed radical aryldifluoromethylation of N-arylacrylamides with S-(difluoromethyl)sulfonium salt.

A facile and highly efficient visible-light photoredox-catalyzed protocol for aryldifluoromethylation of acrylamides was developed using S-(difluoromethyl)sulfonium salt as the difluoromethyl source. With this method, pharmaceutically interesting CF2H-containing oxindoles were readily accessed from N-arylacrylamides, and this method featured mild reaction conditions, a broad scope of substrates, good tolerance of functional groups, and good to excellent yields. Control experiments revealed that this protocol proceeded through a difluoromethylation/cyclization cascade process.

Unveiling breast cancer risk profiles: a survival clustering analysis empowered by an online web application.

Aim: To develop a shiny app for doctors to investigate breast cancer treatments through a new approach by incorporating unsupervised clustering and survival information. Materials & methods: Analysis is based on the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset, which contains 1726 subjects and 22 variables. Cox regression was used to identify survival risk factors for K-means clustering. Logrank tests and C-statistics were compared across different cluster numbers and Kaplan-Meier plots were presented. Results & conclusion: Our study fills an existing void by introducing a unique combination of unsupervised learning techniques and survival information on the clinician side, demonstrating the potential of survival clustering as a valuable tool in uncovering hidden structures based on distinct risk profiles.

Population impact of fine particulate matter on tuberculosis risk in China: a causal inference.

BACKGROUND: Previous studies have suggested the potential association between air pollution and tuberculosis incidence, but this association remains inconclusive and evidence to assess causality is particularly lacking. We aimed to draw causal inference between fine particulate matter less than 2.5 µm in diameter (PM2.5) and tuberculosis in China. METHODS: Granger causality (GC) inference was performed within vector autoregressive models at levels and/or first-differences using annual national aggregated data during 1982-2019, annual provincial aggregated data during 1982-2019 and monthly provincial aggregated data during 2004-2018. Convergent cross-mapping (CCM) approach was used to determine the backbone nonlinear causal association based on the monthly provincial aggregated data during 2004-2018. Moreover, distributed lag nonlinear model (DLNM) was applied to quantify the causal effects. RESULTS: GC tests identified PM2.5 driving tuberculosis dynamics at national and provincial levels in Granger sense. Empirical dynamic modeling provided the CCM causal intensity of PM2.5 effect on tuberculosis at provincial level and demonstrated that PM2.5 had a positive effect on tuberculosis incidence. Then, DLNM estimation demonstrated that the PM2.5 exposure driven tuberculosis risk was concentration- and time-dependent in a nonlinear manner. This result still held in the multi-pollutant model. CONCLUSIONS: Causal inference showed that PM2.5 exposure driving tuberculosis, which showing a concentration gradient change. Air pollutant control may have potential public health benefit of decreasing tuberculosis burden.

Diagnostic value of peripheral TiM-3, NT proBNP, and Sestrin2 testing in left-to-right shunt congenital heart disease with heart failure.

BACKGROUND: Left-to-right shunt congenital heart disease is more likely to induce recurrent respiratory infections in the patients which exacerbate pulmonary hypertension and thereby impairs cardiac function. It is urgent to explore a non-invasive and accurate diagnostic method that can show the cardiac anatomy and associated malformations in clinical research. OBJECTIVE: To determine the diagnostic value of peripheral mucin domain protein-3 (Tim-3), N-terminal pro-brain natriuretic peptide (NT proBNP), sestrin2 testing in patients with the left-to-right shunt congenital heart disease and heart failure. METHODS: Fifty-two neonates with with left to right shunt congenital heart disease and 30 healthy neonates were enrolled. Blood samples were collected within 24 h of admission from newborns for determining the content of TiM-3, NT proBNP, and Sestrin2. Analyzing the ROC curve provided insight into the diagnostic accuracy. Both a Spearman's rank correlation test and a logistic regression analysis were carried out. RESULTS: TiM-3, NT proBNP, and Sestrin2 levels in peripheral blood were statistically different in the three groups (P < 0.05). There were significant differences in LVEF and LVFS among the three groups (P < 0.05). When used to diagnose heart failure in conjunction with left-to-right shunt congenital heart disease, TiM-3, NT proBNP, and Sestrin2 exhibited sensitivity of 58.3, 58.3, and 83.3%, respectively, and specificity of 85.0, 72.5, and 70.0%. ROC curve analysis showed that the AUCs of Tim-3, NT proBNP, and sestrin2 in predicting the outcome of left-to-right shunted congenital heart disease combined with heart failure were 0.744 (95% CI, 0.580 to 0.908), 0.608 (95% CI, 0.359 to 0.857), respectively 0.744 (95% CI 0.592 to 0.896). CONCLUSION: Tim-3, NT proBNP, and sestrin2 can accurately differentiate heart failure from non-combined heart failure from left-to-right shunt congenital heart disease.

Loss of SIRT5 promotes bile acid-induced immunosuppressive microenvironment and hepatocarcinogenesis.

BACKGROUND & AIMS: The liver is a metabolically active organ and is also 'tolerogenic', exhibiting sophisticated mechanisms of immune regulation that prevent pathogen attacks and tumorigenesis. How metabolism impacts the tumor microenvironment (TME) in hepatocellular carcinoma (HCC) remains understudied. METHODS: We investigated the role of the metabolic regulator SIRT5 in HCC development by conducting metabolomic analysis, gene expression profiling, flow cytometry and immunohistochemistry analyses in oncogene-induced HCC mouse models and human HCC samples. RESULTS: We show that SIRT5 is downregulated in human primary HCC samples and that Sirt5 deficiency in mice synergizes with oncogenes to increase bile acid (BA) production, via hypersuccinylation and increased BA biosynthesis in the peroxisomes of hepatocytes. BAs act as a signaling mediator to stimulate their nuclear receptor and promote M2-like macrophage polarization, creating an immunosuppressive TME that favors tumor-initiating cells (TICs). Accordingly, high serum levels of taurocholic acid correlate with low SIRT5 expression and increased M2-like tumor-associated macrophages (TAMs) in HCC patient samples. Finally, administration of cholestyramine, a BA sequestrant and FDA-approved medication for hyperlipemia, reverses the effect of Sirt5 deficiency in promoting M2-like polarized TAMs and liver tumor growth. CONCLUSIONS: This study uncovers a novel function of SIRT5 in orchestrating BA metabolism to prevent tumor immune evasion and suppress HCC development. Our results also suggest a potential strategy of using clinically proven BA sequestrants for the treatment of patients with HCC, especially those with decreased SIRT5 and abnormally high BAs. LAY SUMMARY: Hepatocellular caricinoma (HCC) development is closely linked to metabolic dysregulation and an altered tumor microenvironment. Herein, we show that loss of the metabolic regulator Sirt5 promotes hepatocarcinogenesis, which is associated with abnormally elevated bile acids and subsequently an immunosuppressive microenvironment that favors HCC development. Targeting this mechanism could be a promising clinical strategy for HCC.

Robust radiosensitization of hemoglobin-curcumin nanoparticles suppresses hypoxic hepatocellular carcinoma.

BACKGROUND: Radioresistance inducing by hypoxic microenvironment of hepatocellular carcinoma is a major obstacle to clinical radiotherapy. Advanced nanomedicine provides an alternative to alleviate the hypoxia extent of solid tumor, even to achieve effective synergistic treatment when combined with chemotherapy or radiotherapy. RESULTS: Herein, we developed a self-assembled nanoparticle based on hemoglobin and curcumin for photoacoustic imaging and radiotherapy of hypoxic hepatocellular carcinoma. The fabricated nanoparticles inhibited hepatoma migration and vascular mimics, and enhanced the radiosensitivity of hypoxic hepatoma cells in vitro via repressing cell proliferation and DNA damage repair, as well as inducing apoptosis. Benefit from oxygen-carrying hemoglobin combined with polyphenolic curcumin, the nanoparticles also effectively enhanced the photoacoustic contrast and the efficacy of radiotherapy for hepatocellular carcinoma in vivo. CONCLUSIONS: Together, the current study offered a radiosensitization platform for optimizing the efficacy of nanomedicines on hypoxic radioresistant tumor.

Linalool inhibits the angiogenic activity of endothelial cells by downregulating intracellular ATP levels and activating TRPM8.

Angiogenesis crucially contributes to various diseases, such as cancer and diabetic retinopathy. Hence, anti-angiogenic therapy is considered as a powerful strategy against these diseases. Previous studies reported that the acyclic monoterpene linalool exhibits anticancer, anti-inflammatory and anti-oxidative activity. However, the effects of linalool on angiogenesis still remain elusive. Therefore, we investigated the action of (3R)-(-)-linalool, a main enantiomer of linalool, on the angiogenic activity of human dermal microvascular endothelial cells (HDMECs) by a panel of angiogenesis assays. Non-cytotoxic doses of linalool significantly inhibited HDMEC proliferation, migration, tube formation and spheroid sprouting. Linalool also suppressed the vascular sprouting from rat aortic rings. In addition, Matrigel plugs containing linalool exhibited a significantly reduced microvessel density 7 days after implantation into BALB/c mice. Mechanistic analyses revealed that linalool promotes the phosphorylation of extracellular signal-regulated kinase (ERK), downregulates the intracellular level of adenosine triphosphate (ATP) and activates the transient receptor potential cation channel subfamily M (melastatin) member (TRPM)8 in HDMECs. Inhibition of ERK signaling, supplementation of ATP and blockade of TRPM8 significantly counteracted linalool-suppressed HDMEC spheroid sprouting. Moreover, ATP supplementation completely reversed linalool-induced ERK phosphorylation. In addition, linalool-induced ERK phosphorylation inhibited the expression of bone morphogenetic protein (BMP)-2 and linalool-induced TRPM8 activation caused the inhibition of ß1 integrin/focal adhesion kinase (FAK) signaling. These findings indicate an anti-angiogenic effect of linalool, which is mediated by downregulating intracellular ATP levels and activating TRPM8.

A phenotypic risk score for predicting mortality in sickle cell disease.

Risk assessment for patients with sickle cell disease (SCD) remains challenging as it depends on an individual physician's experience and ability to integrate a variety of test results. We aimed to provide a new risk score that combines clinical, laboratory, and imaging data. In a prospective cohort of 600 adult patients with SCD, we assessed the relationship of 70 baseline covariates to all-cause mortality. Random survival forest and regularised Cox regression machine learning (ML) methods were used to select top predictors. Multivariable models and a risk score were developed and internally validated. Over a median follow-up of 4·3 years, 131 deaths were recorded. Multivariable models were developed using nine independent predictors of mortality: tricuspid regurgitant velocity, estimated right atrial pressure, mitral E velocity, left ventricular septal thickness, body mass index, blood urea nitrogen, alkaline phosphatase, heart rate and age. Our prognostic risk score had superior performance with a bias-corrected C-statistic of 0·763. Our model stratified patients into four groups with significantly different 4-year mortality rates (3%, 11%, 35% and 75% respectively). Using readily available variables from patients with SCD, we applied ML techniques to develop and validate a mortality risk scoring method that reflects the summation of cardiopulmonary, renal and liver end-organ damage. Trial Registration: ClinicalTrials.gov Identifier: NCT#00011648.

Apoferritin-Engineered Nanoprobe for Tumor-Targeted Triple-NIR Imaging and Phototherapy.

Considering that pathological hallmarks are directly related to structural and chemical information of tumor, noninvasive, real-time, spatially resolved quantitative chemical imaging is significant for treatment decisions. The discovery of the transparency window of biological tissues and the advancement of near-infrared technology provide exciting prospects for in vivo imaging. Herein, an engineering apoferritin-conjugated cypate nanoprobe is fabricated for near-infrared photoacoustic imaging and fluorescence imaging in the first and second window. As the analogue of indocyanine green, dicarboxylic cypate is directly conjugated with the apoferritin molecules for forming assembly nanoprobes. Resulting from the intrinsic targeting and optical capacity of the nanoprobes, the triple near-infrared imaging can perform multimeasurements of the target analyte in real-time. This imaging methodology not only provides the structural background information of the tumor, each pixel also contains quantitative in situ information of the tumor. In particular, part of the absorbed light energy is released as heat energy in the near-infrared photoacoustic imaging process. The constructed triple near-infrared nanoprobes therefore naturally navigate the photothermal treatment plan of tumor and finally realize the efficient assistance of tumor photothermal ablation. The tumor metabolomics reveal that the nanoprobe-assisted tumor ablation has a potential mechanism toward glutamine- and phenylalanine-related metabolism perturbation and the disordered oxidative stress state. The tumor-specific bioconjugate nanoprobes hold great potential as a versatile theranostic platform for tumor imaging and therapy.