Recent Progress of Bioinspired Cell Membrane in Cancer Immunotherapy.

By modifying immune cells, immunotherapy can activate immune response to establish long-term immune memory and prevent tumor recurrence. However, their effectiveness is largely constricted by the poor immunogenicity, immune escape, and immune tolerance of the tumor. This is related to the characteristics of the tumor itself, such as genome instability and mutation. The combination of various nanocarriers with tumor immunotherapy is beneficial for overcoming the shortcomings of traditional immunotherapy. Nanocarriers coated by cell membranes can extend blood circulation time, improve ability to evade immune clearance, and enhance targeting, thus significantly enhancing the efficacy of immunotherapy and showing great potential in tumor immunotherapy. This article reviews the application research progress of different types of cell membrane-modified nanocarriers in tumor immunotherapy, immunotherapy combination therapy, and tumor vaccines, and provides prospects for future research.

Energy evolution mechanism of structural surfaces in sandstones with different dips based on the energy principle.

A uniaxial compression test was conducted on sandstone specimens at various inclination angles to determine the energy evolution characteristics during deformation and damage. Based on the principle of minimum energy dissipation, an intrinsic model incorporating the damage threshold was developed to investigate the mechanical properties of sandstone at different inclination angles, and the energy damage evolution during deformation and damage. This study indicated that when the inclination angle of the structural surface remained below 40°, sandstone exhibited varying mechanical properties based on different inclination angles. The peak strain was positively correlated with the inclination angle, whereas the compressive strength and modulus of elasticity showed negative correlations. From an energy perspective, the deformation and damage of sandstone under external loading entail processes of energy input, accumulation, and dissipation. Moreover, higher inclination angles of the structural surface resulted in a smaller absorbed peak strain and a reduced proportion of dissipated energy relative to the energy input, thereby affecting the evolution of energy damage throughout the process. As the inclination angle of the structural surface increased, the absorbed total strain at the peak value decreased, whereas the proportion of the dissipated energy increased. Additionally, the damage threshold and critical value of the rock specimens increased with the inclination angle. The critical value, a composite index comprising the peak strain, compressive strength, and elastic modulus, also increased accordingly. These findings can offer a novel perspective for analyzing geological disasters triggered by fissure zones within underground rock formations.

Mechanical characteristics and energy evolution in a rock mass with a weak structural plane.

The present aims to investigate the mechanical characteristics and energy evolution in rock masses containing weak structural planes under conventional triaxial loading conditions. Using a fluid-solid coupling test system of coal rock, numerous conventional triaxial compression tests were performed on rock masses at various dip angles of the structural plane. The obtained empirical outcomes revealed that the deviatoric stress-strain curve of the weak structural plane rock mass with an inclination angle greater than 20° rises step-by-step. On the macro level, slip-stability occurs on the upper and lower parts of the rock mass on the weak structural plane. Then mechanism of the slip-stability phenomenon is explored by analyzing the stress level in the rock mass with various inclination angles. It is found that the energy evolution during deformation and failure reflects the damaged state of the rock. Accordingly, the concept of 'slip dissipation energy' is proposed, and the values of each energy are calculated. The results have a good correspondence with the deviatoric stress-strain curve. Furthermore, it was found that the energy evolution of rock mass with a weak structural plane can be primarily classified into four stages, including storage of the initial energy, slip dissipation, abrupt increase in the pre-peak dissipation energy, and sudden drop in post-peak energy. Rock masses with various levels of dip angles exhibit similar elastic strain energy and dissipation energy at the peak point, demonstrating that energy evolution is dominated by energy storage and dissipation. At the same time, a negative correlation is observed between the structural plane dip angle and the occurrence of instantaneous impact instability failure in rock masses, indicating that a greater dip angle makes the rock mass less prone to experiencing instantaneous impact instability failure. This article provides a new idea for analyzing the geological disasters caused by external disturbances.

Modelling porcine NAFLD by deletion of leptin and defining the role of AMPK in hepatic fibrosis.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent cause of chronic hepatic disease and results in non-alcoholic steatohepatitis (NASH), which progresses to fibrosis and cirrhosis. Although the Leptin deficient rodent models are widely used in study of metabolic syndrome and obesity, they fail to develop liver injuries as in patients. METHODS: Due to the high similarity with humans, we generated Leptin-deficient (Leptin-/-) pigs to investigate the mechanisms and clinical trials of obesity and NAFLD caused by Leptin. RESULTS: The Leptin-/- pigs showed increased body fat and significant insulin resistance at the age of 12 months. Moreover, Leptin-/- pig developed fatty liver, non-alcoholic steatohepatitis and hepatic fibrosis with age. Absence of Leptin in pig reduced the phosphorylation of JAK2-STAT3 and AMPK. The inactivation of JAK2-STAT3 and AMPK enhanced fatty acid ß-oxidation and leaded to mitochondrial autophagy respectively, and both contributed to increased oxidative stress in liver cells. In contrast with Leptin-/- pig, although Leptin deletion in rat liver inhibited JAK2-STAT3 phosphorylation, the activation of AMPK pathway might prevent liver injury. Therefore, ß-oxidation, mitochondrial autophagy and hepatic fibrosis did not occurred in Leptin-/- rat livers. CONCLUSIONS: The Leptin-deficient pigs presents an ideal model to illustrate the full spectrum of human NAFLD. The activity of AMPK signaling pathway suggests a potential target to develop new strategy for the diagnosis and treatment of NAFLD.

Spike Protein Fragments Promote Alzheimer's Amyloidogenesis.

Alzheimer's disease (AD) is a major cause of dementia inducing memory loss, cognitive decline, and mortality among the aging population. While the amyloid aggregation of peptide Aß has long been implicated in neurodegeneration in AD, primarily through the production of toxic polymorphic aggregates and reactive oxygen species, viral infection has a less explicit role in the etiology of the brain disease. On the other hand, while the COVID-19 pandemic is known to harm human organs and function, its adverse effects on AD pathobiology and other human conditions remain unclear. Here we first identified the amyloidogenic potential of 1058HGVVFLHVTYV1068, a short fragment of the spike protein of SARS-CoV-2 coronavirus. The peptide fragment was found to be toxic and displayed a high binding propensity for the amyloidogenic segments of Aß, thereby promoting the aggregation and toxicity of the peptide in vitro and in silico, while retarding the hatching and survival of zebrafish embryos upon exposure. Our study implicated SARS-CoV-2 viral infection as a potential contributor to AD pathogenesis, a little explored area in our quest for understanding and overcoming Long Covid.

Amyloid Aggregation and Liquid-Liquid Phase Separation from the Perspective of Phase Transitions.

Amyloid aggregation describes the aberrant self-assembly of peptides into ordered fibrils characterized by cross-ß spine cores and is associated with many neurodegenerative diseases and Type 2 diabetes. Oligomers, populated during the early stage of aggregation, are found to be more cytotoxic than mature fibrils. Recently, many amyloidogenic peptides have been reported to undergo liquid-liquid phase separation (LLPS)─a biological process important for the compartmentalization of biomolecules in living cells─prior to fibril formation. Understanding the relationship between LLPS and amyloid aggregation, especially the formation of oligomers, is essential for uncovering disease mechanisms and mitigating amyloid toxicity. In this Perspective, available theories and models of amyloid aggregation and LLPS are first briefly reviewed. By drawing analogies to gas, liquid, and solid phases in thermodynamics, a phase diagram of protein monomer, droplet, and fibril states separated by coexistence lines can be inferred. Due to the high free energy barrier of fibrillization kinetically delaying the formation of fibril seeds out of the droplets, a "hidden" monomer-droplet coexistence line extends into the fibril phase. Amyloid aggregation can then be described as the equilibration process from the initial "out-of-equilibrium" state of a homogeneous solution of monomers to the final equilibrium state of stable amyloid fibrils coexisting with monomers and/or droplets via the formation of metastable or stable droplets as the intermediates. The relationship between droplets and oligomers is also discussed. We suggest that the droplet formation of LLPS should be considered in future studies of amyloid aggregation, which may help to better understand the aggregation process and develop therapeutic strategies to mitigate amyloid toxicity.

Continuous Hypobaric Hypoxia may Promote Atherosclerosis Progression in Apolipoprotein E-deficient Mice.

Background: Intermittent normobaric hypoxia can promote the progression of atherosclerotic plaques. However, the effect of continuous hypobaric hypoxia (CHH), which is a major feature of high-altitude environment, on atherosclerosis has not been investigated thoroughly. Materials and Methods: After eight weeks of high-cholesterol diet, 30 male ApoE-/- mice were randomly divided into control and CHH groups. Mice in the CHH group lived in a hypobaric chamber with an oxygen content of 10% and air pressure of 364 mmhg (equal to 5,800 m altitude above sea level) for 4 weeks, while mice in the control group lived in normoxia condition. Then all mice were euthanized and the atherosclerotic lesion size and plaque stability in the aortic root were assessed. Intraplaque angiogenesis was characterized by immunostaining of CD31 and endomucin, which are identified as specific markers of vascular endothelial cells. Immunohistochemistry and qRT-PCR were performed to measure inflammatory cytokines. Results: Four weeks of CHH exposure promoted the growth of atherosclerotic lesions (p=0.0017) and decreased the stability of atherosclerotic plaques. In CHH group, plaque smooth muscle cells and collagen contents decreased, while plaque macrophages and lipids contents increased significantly (p<0.001). The contents of CD31 (p=0.0379) and endomucin (p=0.0196) in the plaque was higher in the CHH group and correlated with angiogenesis progression. Further, the content of monocyte chemotactic protein-1 (p=0.0376) and matrix metalloproteinase-2 was significantly higher (p=0.0212) in the CHH group. Conclusions: CHH may accelerate atherosclerosis progression in ApoE-/- mice by promoting angiogenesis and inflammation.

Risk factors associated with left atrial appendage thrombosis in patients with non-valvular atrial fibrillation by transesophageal echocardiography.

PURPOSE: This study investigated possible mechanism of left atrial appendage (LAA) thrombosis and constructed a model to evaluate the future risk of LAA thrombosis and spontaneous echo contrast (SEC) in non-valvular atrial fibrillation (NVAF) patients. METHODS: This retrospective study included 2591 patients diagnosed with NVAF. Patients were divided based on the presence of transesophageal echocardiography (TEE) into a thrombus group, SEC group, and control group. General, biochemical, and echocardiography data of the three groups were analyzed. The variables independently associated with LAA thrombosis and SEC were determined by the logistic regression analysis. A nomogram was constituted based on the regression analysis and the discriminatory ability was analyzed by receiver operating characteristic (ROC) curve. RESULTS: LAA thrombosis and SEC were present in 110 (4.2%) patients and 103 (3.9%) patients, respectively. AF type (OR = 1.857), previous stroke (OR = 1.924), fibrinogen (OR = 1.636), diameters of the left atria (OR = 1.094), left ventricular ejection fraction (OR = 0.938), and LAA maximum caliber (OR = 1.238) resulted as independent risk factors for LAA thrombosis and SEC. The area under curve of the nomogram established by multivariate logistic regression was 0.824. Conclusions; Through the study, 6 independent risk factors related to the LAA thrombosis and SEC were found, and an effective nomogram was constructed to predict the LAA thrombosis and SEC in NVAF patients.

Deficiency of neuropeptide Y attenuates neointima formation after vascular injury in mice.

BACKGROUND: Restenosis after percutaneous coronary intervention (PCI) limits therapeutic revascularization. Neuropeptide Y (NPY), co-stored and co-released with the sympathetic nervous system, is involved in this process, but its exact role and underlying mechanisms remain to be fully understood. This study aimed to investigate the role of NPY in neointima formation after vascular injury. METHODS: Using the left carotid arteries of wild-type (WT, NPY-intact) and NPY-deficient (NPY-/-) mice, ferric chloride-mediated carotid artery injury induced neointima formation. Three weeks after injury, the left injured carotid artery and contralateral uninjured carotid artery were collected for histological analysis and immunohistochemical staining. RT-qPCR was used to detect the mRNA expression of several key inflammatory markers and cell adhesion molecules in vascular samples. Raw264.7 cells were treated with NPY, lipopolysaccharide (LPS), and lipopolysaccharide-free, respectively, and RT-qPCR was used to detect the expression of these inflammatory mediators. RESULTS: Compared with WT mice, NPY-/- mice had significantly reduced neointimal formation three weeks after injury. Mechanistically, immunohistochemical analysis showed there were fewer macrophages and more vascular smooth muscle cells in the neointima of NPY-/- mice. Moreover, the mRNA expression of key inflammatory markers such as interleukin-6 (IL-6), transforming growth factor-ß1 (TGF-ß1), and intercellular adhesion molecule-1 (ICAM-1) was significantly lower in the injured carotid arteries of NPY-/- mice, compared to that in the injured carotid arteries of WT mice. In RAW264.7 macrophages, NPY significantly promoted TGF-ß1 mRNA expression under unactivated but not LPS-stimulated condition. CONCLUSIONS: Deletion of NPY attenuated neointima formation after artery injury, at least partly, through reducing the local inflammatory response, suggesting that NPY pathway may provide new insights into the mechanism of restenosis.

Differential Binding and Conformational Dynamics of Tau Microtubule-Binding Repeats with a Preformed Amyloid-ß Fibril Seed.

Both senile plaques formed by amyloid-ß (Aß) and neurofibrillary tangles (NFTs) comprised of tau are pathological hallmarks of Alzheimer's disease (AD). The accumulation of NFTs better correlates with the loss of cognitive function than senile plaques, but NFTs are rarely observed without the presence of senile plaques. Hence, cross-seeding of tau by preformed Aß amyloid fibril seeds has been proposed to drive the aggregation of tau and exacerbate AD progression, but the molecular mechanism remains unknown. Here, we first identified cross-interaction hotspots between Aß and tau using atomistic discrete molecular dynamics simulations (DMD) and confirmed the critical role of the four microtubule-binding repeats of tau (R1-R4) in the cross-interaction with Aß. We further investigated the binding structure and dynamics of each tau repeat with a preformed Aß fibril seed. Specifically, R1 and R3 preferred to bind the Aß fibril lateral surface instead of the elongation end. In contrast, R2 and R4 had higher binding propensities to the fibril elongation end than the lateral surface, enhancing ß-sheet content by forming hydrogen bonds with the exposed hydrogen bond donors and acceptors. Together, our results suggest that the four repeats play distinct roles in driving the binding of tau to different surfaces of an Aß fibril seed. Binding of tau to the lateral surface of Aß fibril can increase the local concentration, while the binding to the elongation surface promotes ß-sheet formation, both of which reduce the free energy barrier for tau aggregation nucleation and subsequent fibrillization.

Effects of Using Aluminum Sulfate as an Accelerator and Acrylic Acid, Aluminum Fluoride, or Alkanolamine as a Regulator in Early Cement Setting.

Aluminum sulfate was employed as the main accelerator in order to explore new non-chloride and alkali-free cement accelerators. Acrylic acid, aluminum fluoride, or alkanolamine were used as regulators to further accelerate cement setting. The setting time, compressive, and flexural strengths in cement early strength progress were detected, and both the cement (raw material) and hydrated mortar were fully characterized. The cement setting experiments revealed that only loading acrylic acid as the regulator would decrease the setting time of cement and increase the compressive and flexural strengths of mortar, but further introduction of aluminum fluoride or alkanolamine improved this process drastically. In the meantime, structural characterizations indicated that the raw material (cement) used in this work was composed of C3S (alite), while hydrated mortar consisted of quartz and C3A (tricalcium aluminate). During this transformation, the coordination polyhedron of Al3+ was changed from a tetrahedron to octahedron. This work puts forward a significant strategy for promoting the activity of aluminum sulfate in cement setting and would contribute to the future design of new non-chloride and alkali-free cement accelerators.

Failure energy evolution of coal-rock combination with different inclinations.

In this paper, in the deformation and damage process under different confining pressures, the energy evolution characteristics and damage mechanism of coal-rock combinations with different inclination angles are studied. Based on the brittleness indexes of coal rock combinations, the evolution rules between brittleness indexes and the inclination are explored, as well as the confining pressure of coal rock combinations; then, the influence mechanism of the inclination angle of coal rock combinations on the plastic yielding degree, energy dissipation level, crack extension and fracture speed in the pre-peak stage is revealed. The composite specimens are mainly damaged due to oblique shear and accompanied by tensile damage; In the deformation and damage, various energies of coal rock composites are distributed as a negative exponential function of the inclination angle, which is significantly affected by the change of the confining pressure.

Arcuate NPY is involved in salt-induced hypertension via modulation of paraventricular vasopressin and brain-derived neurotrophic factor.

Chronic high salt intake is one of the leading causes of hypertension. Salt activates the release of the key neurotransmitters in the hypothalamus such as vasopressin to increase blood pressure, and neuropepetide Y (NPY) has been implicated in the modulation of vasopressin levels. NPY in the hypothalamic arcuate nucleus (Arc) is best known for its control in appetite and energy homeostasis, but it is unclear whether it is also involved in the development of salt-induced hypertension. Here, we demonstrate that wild-type mice given 2% NaCl salt water for 8 weeks developed hypertension which was associated with marked downregulation of NPY expression in the hypothalamic Arc as demonstrated in NPY-GFP reporter mice as well as by in situ hybridization analysis. Furthermore, salt intake activates neurons in the hypothalamic paraventricular nucleus (PVN) where mRNA expression of brain-derived neurotrophic factor (BDNF) and vasopressin was found to be upregulated, leading to elevated serum vasopressin levels. This finding suggests an inverse correlation between the Arc NPY level and expression of vasopressin and BDNF in the PVN. Specific restoration of NPY by injecting AAV-Cre recombinase into the Arc only of the NPY-targeted mutant mice carrying a loxP-flanked STOP cassette reversed effects of salt intake on vasopressin and BDNF expression, leading to a normalization of salt-dependent blood pressure. In summary, our study uncovers an important Arc NPY-originated neuronal circuitry that could sense and respond to peripheral electrolyte signals and thereby regulate hypertension via vasopressin and BDNF in the PVN.

High-frequency fiber Bragg gating accelerometer and strain sensor-based blast test on a concrete slab.

The blast test is the most direct method of measuring explosive performance and structural safety. Because of long-distance wires and electromagnetic interference, some scattering exists in the blast test using electrical sensors. For this paper, a double-hinge high-frequency fiber Bragg gating (FBG) accelerometer was designed and manufactured to measure the acceleration on a blast-loaded concrete slab. The resonance frequency and sensitiveness of the sensor were determined as 3400 Hz and 6.26 pm/g, respectively. Blasting was performed seven times, with each blast generating the energy equivalent of 50 kg of TNT. The stress waves were obtained from the blast source for distances at 4 m, 6 m, and 8 m. The peak accelerations in test 6 were obtained as 396.21 g, 123.57 g, and 38.88 g, respectively, whereas the propagation velocity of the stress wave was around 2500 m/s. Furthermore, the study was complemented by numerical simulations. The test results were compared with the empirical formula, which validated the reliability and applicability of fiber optical sensors in blast testing. The proposed fiber optical sensors have shown promising results, further boosting their practical applications in blast testing and monitoring structural health following a blast shock.

Inhibition of Amyloid Aggregation and Toxicity with Janus Iron Oxide Nanoparticles.

Amyloid aggregation is a ubiquitous form of protein misfolding underlying the pathologies of Alzheimer's disease (AD), Parkinson's disease (PD) and type 2 diabetes (T2D), three primary forms of human amyloid diseases. While much has been learned about the origin, diagnosis and management of these neurological and metabolic disorders, no cure is currently available due in part to the dynamic and heterogeneous nature of the toxic oligomers induced by amyloid aggregation. Here we synthesized beta casein-coated iron oxide nanoparticles (ßCas IONPs) via a BPA-P(OEGA-b-DBM) block copolymer linker. Using a thioflavin T kinetic assay, transmission electron microscopy, Fourier transform infrared spectroscopy, discrete molecular dynamics simulations and cell viability assays, we examined the Janus characteristics and the inhibition potential of ßCas IONPs against the aggregation of amyloid beta (Aß), alpha synuclein (αS) and human islet amyloid polypeptide (IAPP) which are implicated in the pathologies of AD, PD and T2D. Incubation of zebrafish embryos with the amyloid proteins largely inhibited hatching and elicited reactive oxygen species, which were effectively rescued by the inhibitor. Furthermore, Aß-induced damage to mouse brain was mitigated in vivo with the inhibitor. This study revealed the potential of Janus nanoparticles as a new nanomedicine against a diverse range of amyloid diseases.

A Medium-Frequency Fiber Bragg Grating Accelerometer Based on Flexible Hinges.

Mediumfrequency fiber Bragg grating (FBG) acceleration sensors are used in important applications in mechanical, aerospace and weapon equipment, and have strict requirements in terms of resonance frequency and sensitivity. A novel medium-frequency accelerometer, based on fiber Bragg grating and flexible hinges, is proposed in this paper. The differential structure doubles the sensitivity of the sensor while avoiding temperature effects. The structure model and principle for the sensor are introduced, the sensor's sensing characteristics are theoretically analyzed, and the structure parameters for the sensor are determined through numerical analysis. The sensing experiments show that the resonance frequency of the sensor is approximately 2800 Hz, the sensitivity is 21.8 pm/g in the flat frequency range of 50-1000 Hz, and the proposed sensor has a good temperature self-compensation function and lateral anti-interference capability.

Thrombus management during direct coronary intervention for acute myocardial infarction.

OBJECTIVE: To study the management of thrombus during direct coronary intervention in patients with acute myocardial infarction (AMI). METHODS: We retrospectively analyzed 332 acute myocardial infarction patients receiving coronary artery intervention in our hospital from May 2017 to May 2019. Among them, 221 patients received thrombus aspiration and 111 patients received thrombus aspiration combined with platelet membrane glycoproteins receptor antagonist. The propensity score matching 1:1 nearest neighbor matching method was adopted to match 50 cases of the two methods as the control group and the experimental group, respectively. The incidence rate of intraoperative and postoperative adverse reactions, the effective rate of treatment, the electrocardiogram (ECG) at 1 h after operation, and the echocardiographic results at 1 week after operation were compared between the two groups. RESULTS: The incidence rate of adverse reactions in the experimental group was significantly lower than that in the control group, (P<0.05). The incidence rate of postoperative adverse reactions in the two groups did not statistically differ (P>0.05). The effective rate was found to be substantially higher in the experimental group when compared with that of the control group (P<0.05). The ECG 1 h after operation was in favor of the experimental group (P<0.05). The echocardiography results 1 week after operation were not statistically different in the two groups (P>0.05). CONCLUSION: Thrombus aspiration combined with receptor antagonist yielded a desirable outcome in direct coronary intervention for AMI, and has a high application value.

Hepcidin Upregulation in Lung Cancer: A Potential Therapeutic Target Associated With Immune Infiltration.

Lung cancer has the highest death rate among cancers globally. Hepcidin is a fascinating regulator of iron metabolism; however, the prognostic value of hepcidin and its correlation with immune cell infiltration in lung cancer remain unclear. Here, we comprehensively clarified the prognostic value and potential function of hepcidin in lung cancer. Hepcidin expression was significantly increased in lung cancer. High hepcidin expression was associated with sex, age, metastasis, and pathological stage and significantly predicted an unfavorable prognosis in lung cancer patients. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) results suggested that hepcidin is involved in the immune response. Furthermore, hepcidin expression was positively correlated with the infiltration levels of immune cells and the expression of diverse immune cell marker sets. Importantly, hepcidin may affect prognosis partially by regulating immune infiltration in lung cancer patients. Hepcidin may serve as a candidate prognostic biomarker for determining prognosis associated with immune infiltration in lung cancer.

Risk prediction in medically treated chronic thromboembolic pulmonary hypertension.

BACKGROUND: At present, there is no generally accepted comprehensive prognostic risk prediction model for medically treated chronic thromboembolic pulmonary hypertension (CTEPH) patients. METHODS: Consecutive medically treated CTEPH patients were enrolled in a national multicenter prospective registry study from August 2009 to July 2018. A multivariable Cox proportional hazards model was utilized to derive the prognostic model, and a simplified risk score was created thereafter. Model performance was evaluated in terms of discrimination and calibration, and compared to the Swedish/COMPERA risk stratification method. Internal and external validation were conducted to validate the model performance. RESULTS: A total of 432 patients were enrolled. During a median follow-up time of 38.73 months (IQR: 20.79, 66.10), 94 patients (21.8%) died. The 1-, 3-, and 5-year survival estimates were 95.5%, 83.7%, and 70.9%, respectively. The final model included the following variables: the Swedish/COMPERA risk stratum (low-, intermediate- or high-risk stratum), pulmonary vascular resistance (PVR, ≤ or > 1600 dyn·s/cm5), total bilirubin (TBIL, ≤ or > 38 µmol/L) and chronic kidney disease (CKD, no or yes). Compared with the Swedish/COMPERA risk stratification method alone, both the derived model [C-index: 0.715; net reclassification improvement (NRI): 0.300; integrated discriminatory index (IDI): 0.095] and the risk score (C-index: 0.713; NRI: 0.300; IDI: 0.093) showed improved discriminatory power. The performance was validated in a validation cohort of 84 patients (C-index = 0.707 for the model and 0.721 for the risk score). CONCLUSIONS: A novel risk stratification strategy can serve as a useful tool for determining prognosis and guide management for medically treated CTEPH patients. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT01417338).

Ferroptosis inducer erastin sensitizes NSCLC cells to celastrol through activation of the ROS-mitochondrial fission-mitophagy axis.

Despite recent progress in non-small-cell lung cancer (NSCLC) treatment, treatment outcomes remain poor, mainly because of treatment resistance or toxicity. Erastin is a ferroptosis inducer that has shown promising cytotoxic effects in various types of cancers, including NSCLC. Celastrol is a triterpene extracted from the Tripterygium wilfordii that exhibits potential anticancer activity. However, the side effects of celastrol are severe and limit its clinical application. Combination therapy is a promising strategy to overcome the compensatory mechanisms and unwanted off-target effects. In the present study, we found that erastin synergized with celastrol to induce cell death at nontoxic concentrations. The combined treatment with celastrol and erastin significantly increased reactive oxygen species (ROS) generation, disrupted mitochondrial membrane potential, and promoted mitochondrial fission. Furthermore, cotreatment with erastin and celastrol initiated ATG5/ATG7-dependent autophagy, PINK1/Parkin-dependent mitophagy, and the expression of heat shock proteins (HSPs) in an HSF1-dependent manner. HSF1 knockdown further enhanced cell death in vitro and inhibited tumor growth in vivo. Our findings indicate that the combination of celastrol with erastin may represent a novel therapeutic regimen for patients with NSCLC and warrants further clinical evaluation.