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Decoherence and imperfect control are crucial challenges for quantum technologies. Common protection strategies rely on noise temporal autocorrelation, which is not optimal if other correlations are present. We develop and demonstrate experimentally a strategy that uses the cross-correlation of two noise sources. Utilizing destructive interference of cross-correlated noise extends the coherence time tenfold, improves control fidelity, and surpasses the state-of-the-art sensitivity for high frequency quantum sensing, significantly expanding the applicability of noise protection strategies.
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Ionising radiation exposure can lead to acute haematopoietic radiation syndrome. Despite significant advancements in the field of radioprotection, no drugs with high efficacy and low toxicity have yet been approved by the Food and Drug Administration. FG-4592, as a proline hydroxylase inhibitor, may play an important role in radioprotection of the haematopoietic system. Mice were peritoneal injected with FG-4592 or normal saline. After irradiation, the survival time, body weight, peripheral blood cell and bone marrow cell (BMC) count, cell apoptosis, pathology were analysed and RNA-sequence technique (RNA-Seq) was conducted to explore the mechanism of FG-4592 in the haematopoietic system. Our results indicated that FG-4592 improved the survival rate and weight of irradiated mice and protected the spleen, thymus and bone marrow from IR-induced injury. The number of BMCs was increased and protected against IR-induced apoptosis. FG-4592 also promoted the recovery of the blood system and erythroid differentiation. The results of RNA-Seq and Western blot showed that the NF-κB signalling pathway and hypoxia-inducible factor-1 (HIF-1) signalling pathway were upregulated by FG-4592. Meanwhile, RT-PCR results showed that FG-4592 could promote inflammatory response significantly. FG-4592 exhibited radioprotective effects in the haematopoietic system by promoting inflammatory response and targeting the NF-κB, HIF signalling pathway.
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Apoptosis , Radiación Ionizante , Protectores contra Radiación , Animales , Ratones , Protectores contra Radiación/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Transducción de Señal/efectos de los fármacos , FN-kappa B/metabolismo , Masculino , Ratones Endogámicos C57BL , Sistema Hematopoyético/efectos de los fármacos , Sistema Hematopoyético/efectos de la radiación , Síndrome de Radiación Aguda/prevención & control , Síndrome de Radiación Aguda/tratamiento farmacológico , Hematopoyesis/efectos de los fármacos , Hematopoyesis/efectos de la radiación , Traumatismos Experimentales por Radiación/prevención & control , Traumatismos Experimentales por Radiación/metabolismo , Irradiación Corporal Total , Glicina/análogos & derivados , IsoquinolinasRESUMEN
Chronic kidney disease (CKD) poses a major global public health challenge. The World Health Organization's data shows that CKD affects about 10% of the world's population, particularly in low- and middle-income countries. Due to limited access to diagnosis and treatment, CKD has become the 12th leading cause of death worldwide. The advanced stage of CKD can lead to kidney failure, which is clinically referred to as end-stage renal disease (ESRD). In such cases, patients can only sustain life through dialysis or kidney transplantation. However, the long-term affordability of these treatments remains low. Moreover, the effectiveness of kidney transplantation is modest, posing a significant treatment barrier in resource-limited settings, and significantly impacting patient survival. To address this issue, we suggest using dietary supplementation of the trace element zinc to impede CKD development and prolong patient survival.
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Suplementos Dietéticos , Insuficiencia Renal Crónica , Zinc , Humanos , Zinc/uso terapéutico , Zinc/deficiencia , Zinc/administración & dosificación , Insuficiencia Renal Crónica/terapia , Insuficiencia Renal Crónica/complicaciones , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/terapia , Oligoelementos/administración & dosificación , Oligoelementos/uso terapéutico , Trasplante de Riñón , Diálisis RenalRESUMEN
The electric dipole moment (EDM) plays a crucial role in determining the interaction strength of an atom with electric fields, making it paramount to quantum technologies based on coherent atomic control. We propose a scheme for engineering the potential in a Paul trap to realize a two-level quantum system with a giant EDM formed by the motional states of a trapped electron. We show that, under realistic experimental conditions, our system exhibits enhanced EDMs compared to those attainable with Rydberg atoms, serving as a complementary counterpart in the megahertz (MHz) resonance-frequency range. Furthermore, we show that such artificial atomic dipoles can be efficiently initialized, read out, and coherently controlled, thereby providing a potential platform for quantum technologies such as ultrahigh-sensitivity electric-field sensing.
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To determine whether sarcoplasmic proteins affected water migration in myofibrils during air-drying, with protein denaturation as an indicator of sarcoplasmic protein changes, the extent of sarcoplasmic protein changes in lamb during air-drying was first studied. The results showed that sarcoplasmic protein's thermal stability decreased and secondary structure changed, indicating sarcoplasmic protein denatured in lamb during air-drying (35 °C, 60% RH, 3 m/s wind speed). Subsequently, the effect of sarcoplasmic protein solutions, dried at different times and rates, on myofibril protein-water interaction was studied in vitro. Two sets of sarcoplasmic protein solutions were dried for 0, 3, 6, and 9 h in a drying oven, resulting in different degrees of change. These two sets with higher or lower drying rates were achieved by controlling the contact area between sarcoplasmic protein solution and air. These dried sarcoplasmic protein solutions were then mixed with extracted myofibril and incubated for 2 h. The results showed a significant increase in T21 relaxation time of the incubation system when sarcoplasmic protein solution was dried at 35 °C for 3 h. This indicated that myofibrillar protein-water interaction was weakened, facilitating water migration from the inside to the outside of myofibrils. The denaturation degree of sarcoplasmic proteins was slowed by a higher drying rate, thereby alleviating the increase in the amount of immobile water within myofibrils when dried for 6 h. In conclusion, the properties of sarcoplasmic proteins were influenced by both drying rate and time, thereby influencing the water migration within myofibrils during air-drying.
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PURPOSE: This study aimed to evaluate the ability of MRI-based intratumoral and peritumoral radiomics features of liver tumors to differentiate between hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) and to predict ICC differentiation. METHODS: This study retrospectively collected 87 HCC patients and 75 ICC patients who were confirmed pathologically. The standard region of interest (ROI) of the lesion drawn by the radiologist manually shrank inward and expanded outward to form multiple ROI extended regions. A three-step feature selection method was used to select important radiomics features and convolution features from extended regions. The predictive performance of several machine learning classifiers on dominant feature sets was compared. The extended region performance was assessed by area under the curve (AUC), specificity, sensitivity, F1-score and accuracy. RESULTS: The performance of the model is further improved by incorporating convolution features. Compared with the standard ROI, the extended region obtained better prediction performance, among which 6 mm extended region had the best prediction ability (Classification: AUC = 0.96, F1-score = 0.94, Accuracy: 0.94; Grading: AUC = 0.94, F1-score = 0.93, Accuracy = 0.89). CONCLUSION: Larger extended region and fusion features can improve tumor predictive performance and have potential value in tumor radiology.
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Neoplasias de los Conductos Biliares , Carcinoma Hepatocelular , Colangiocarcinoma , Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/patología , Estudios Retrospectivos , Radiómica , Imagen por Resonancia Magnética/métodos , Conductos Biliares Intrahepáticos/patologíaRESUMEN
PURPOSES: Radiotherapy can induce tumor cell autophagy, which might impair the antitumoral effect. This study aims to investigate the effect of autophagy inhibition on the targeted radionuclide therapy (TRT) efficacy of 131I-FAP-2286 in pancreatic cancer. METHODS: Human pancreatic cancer PANC-1 cells were exposed to 131I-FAP-2286 radiotherapy alone or with the autophagy inhibitor 3-MA. The autophagy level and proliferative activity of PANC-1 cells were analyzed. The pancreatic cancer xenograft-bearing nude mice were established by the co-injection of PANC-1 cells and pancreatic cancer-associated fibroblasts (CAFs), and then were randomly divided into four groups and treated with saline (control group), 3-MA, 131I-FAP-2286 and 131I-FAP-2286 + 3-MA, respectively. SPECT/CT imaging was performed to evaluate the bio-distribution of 131I-FAP-2286 in pancreatic cancer-bearing mice. The therapeutic effect of tumor was evaluated by 18F-FDG PET/CT imaging, tumor volume measurements, and the hematoxylin and eosin (H&E) staining, and immunohistochemical staining assay of tumor tissues. RESULTS: 131I-FAP-2286 inhibited proliferation and increased the autophagy level of PANC-1 cells in a dose-dependent manner. 3-MA promoted 131I-FAP-2286-induced apoptosis of PANC-1 cells via suppressing autophagy. SPECT/CT imaging of pancreatic cancer xenograft-bearing nude mice showed that 131I-FAP-2286 can target the tumor effectively. According to 18F-FDG PET/CT imaging, the tumor growth curves and immunohistochemical analysis, 131I-FAP-2286 TRT was capable of suppressing the growth of pancreatic tumor accompanying with autophagy induction, but the addition of 3-MA enabled 131I-FAP-2286 to achieve a better therapeutic effect along with the autophagy inhibition. In addition, 3-MA alone did not inhibit tumor growth. CONCLUSIONS: 131I-FAP-2286 exposure induces the protective autophagy of pancreatic cancer cells, and the application of autophagy inhibitor is capable of enhancing the TRT therapeutic effect.
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Fluorodesoxiglucosa F18 , Neoplasias Pancreáticas , Animales , Humanos , Ratones , Autofagia , Línea Celular Tumoral , Ratones Desnudos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Tomografía Computarizada por Tomografía de Emisión de Positrones , Radioisótopos/farmacología , Radioisótopos/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
AIM: To identify age-matched healthy volunteers, non-cirrhotic chronic liver disease (CLD) and cirrhotic patients based on portal hemodynamic parameters using 4D flow MRI. METHODS: A total of 10 age-matched healthy volunteers and 69 CLD patients were enrolled and underwent 4D flow MRI prospectively. 4D flow MR images were processed by an MD in biomedical engineering working on the GTFlow platform. Portal hemodynamic parameters include net flow (mL/cycle), flow volume per second through the lumen (mL/sec), average flow velocity (cm/sec), and maximum flow velocity (cm/sec). The difference in portal hemodynamic parameters of 4D flow MRI was compared among healthy volunteers, non-cirrhotic CLD patients and patients with cirrhosis by one-way ANOVA or Kruskal-Wallis nonparametric test and post hoc tests. RESULTS: 10 CLD patients without cirrhosis and 56 patients with cirrhosis were eventually included, along with 10 healthy volunteers who were divided into three groups. 3 patients with cirrhosis whose image quality did not meet the requirements were excluded. There were no significant differences in portal hemodynamic parameters among the three groups except portal average velocity (P > 0.05). There was no statistical difference in all portal hemodynamic parameters of 4D flow MRI between healthy volunteers and patients with cirrhosis (P > 0.05). There were significant differences in portal average velocity between non-cirrhotic CLD patients, healthy volunteers and patients with cirrhosis, respectively (11.44±3.93 vs 8.10±2.66, P=0.013; 11.44±3.93 vs 8.60±2.22, P=0.007). CONCLUSION: Portal average velocity obtained by 4D flow MRI can be an auxiliary means to identify cirrhosis in patients with CLD.
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Hemodinámica , Cirrosis Hepática , Imagen por Resonancia Magnética , Vena Porta , Humanos , Vena Porta/fisiopatología , Vena Porta/diagnóstico por imagen , Masculino , Femenino , Persona de Mediana Edad , Hemodinámica/fisiología , Adulto , Imagen por Resonancia Magnética/métodos , Cirrosis Hepática/diagnóstico por imagen , Cirrosis Hepática/fisiopatología , Voluntarios Sanos , Anciano , Estudios Prospectivos , Enfermedad Crónica , Velocidad del Flujo Sanguíneo/fisiología , Estudios de Casos y Controles , Hepatopatías/diagnóstico por imagen , Hepatopatías/fisiopatologíaRESUMEN
BACKGROUND: Intestinal tissue is extremely sensitive to ionizing radiation (IR), which is easy to cause intestinal radiation sickness, and the mortality rate is very high after exposure. Recent studies have found that intestinal immune cells and intestinal stem cells (ISCs) may play a key role in IR-induced intestinal injury. METHODS: C57BL6 mice matched for age, sex and weight were randomly grouped and intraperitoneal injected with PBS, Scleroglucan (125.0 mg/kg) or Anti-mouse IL-17A -InVivo (10 mg/kg), the number of mice in each group was n ≥ 3.Survival time, body weight, pathology, organoids and immune cell markers of the mice after IR (10.0 Gy) were compared, and the mechanism of action in intestinal tissues was verified by transcriptome sequencing. RESULTS: Scleroglucan has significant radiation protective effects on the intestine, including improving the survival rate of irradiated mice, inhibiting the radiation damage of intestinal tissue, and promoting the proliferation and differentiation of intestinal stem cells (ISCs). The results of RNA sequencing suggested that Scleroglucan could significantly activate the immune system and up-regulate the IL-17 and NF-κB signaling pathways. Flow cytometry showed that Scleroglucan could significantly up-regulate the number of Th17 cells and the level of IL-17A in the gut. IL-17A provides radiation protection. After intraperitoneal injection of Scleroglucan and Anti-mouse IL-17A -InVivo, mice can significantly reverse the radiation protection effect of Scleroglucan, down-regulate the molecular markers of intestinal stem cells and the associated markers of DC, Th1 and Th17 cells, and up-regulate the associated markers of Treg and Macrophage cells. CONCLUSION: Scleroglucan may promote the proliferation and regeneration of ISCs by regulating the activation of intestinal immune function mediated by IL-17 signaling pathway and play a protective role in IR-induced injury.
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Glucanos , Traumatismos por Radiación , Protectores contra Radiación , Ratones , Animales , Interleucina-17 , Ratones Endogámicos C57BL , Traumatismos por Radiación/prevención & control , Transducción de Señal , Protectores contra Radiación/farmacología , Protectores contra Radiación/uso terapéutico , Intestinos/patologíaRESUMEN
OBJECTIVES: Intracranial vessel wall enhancement (VWE) on high-resolution magnetic resonance imaging (HRMRI) is associated with the progression and poor prognosis of moyamoya disease (MMD). This study assessed potential risk factors for VWE in MMD. METHODS: We evaluated MMD patients using HRMRI and traditional angiography examinations. The participants were divided into VWE and non-VWE groups based on HRMRI. Logistic regression was performed to compare the risk factors for VWE in MMD. The incidence of cerebrovascular events of the different subgroups according to risk factors was compared using Kaplan-Meier survival and Cox regression. RESULTS: We included 283 MMD patients, 84 of whom had VWE on HRMRI. The VWE group had higher modified Rankin Scale scores at admission (p = 0.014) and a higher incidence of ischaemia and haemorrhage (p = 0.002) than did the non-VWE group. Risk factors for VWE included the ring finger protein 213 (RNF213) p.R4810K variant (odds ratio [OR] 2.01, 95% confidence interval [CI] 1.08-3.76, p = 0.028), hyperhomocysteinaemia (HHcy) (OR 5.08, 95% CI 2.34-11.05, p < 0.001), and smoking history (OR 3.49, 95% CI 1.08-11.31, p = 0.037). During the follow-up of 63.9 ± 13.2 months (median 65 months), 18 recurrent stroke events occurred. Cox regression showed that VWE and the RNF213 p.R4810K variant were risk factors for stroke. CONCLUSION: The RNF213 p.R4810K variant is strongly associated with VWE and poor prognosis in MMD. HHcy and smoking are independent risk factors for VWE. CLINICAL RELEVANCE STATEMENT: Vessel wall enhancement in moyamoya disease is closely associated with poor prognosis, especially related to the ring finger protein 213 p.R4810K variant, hyperhomocysteinaemia, and smoking, providing crucial risk assessment information for the clinic. KEY POINTS: ⢠The baseline presence of vessel wall enhancement is significantly associated with poor prognosis in moyamoya disease. ⢠The ring finger protein 213 p.R4810K variant is strongly associated with vessel wall enhancement and poor prognosis in moyamoya disease. ⢠Hyperhomocysteinaemia and smoking are independent risk factors for vessel wall enhancement in moyamoya disease.
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Enfermedad de Moyamoya , Humanos , Enfermedad de Moyamoya/diagnóstico por imagen , Masculino , Femenino , Factores de Riesgo , Adulto , Persona de Mediana Edad , Angiografía por Resonancia Magnética/métodos , Imagen por Resonancia Magnética/métodos , Adenosina Trifosfatasas/genética , Pronóstico , Estudios Retrospectivos , Hiperhomocisteinemia/complicaciones , Ubiquitina-Proteína LigasasRESUMEN
BACKGROUND: Little is known about the association between stroke and imaging and clinical features in conservatively treated patients with moyamoya disease (MMD). PURPOSE: To investigate independent risk factors for stroke in conservatively treated patients with MMD during a long-term follow-up. STUDY TYPE: Prospective study. SUBJECTS: One hundred sixty conservatively managed patients with MMD (median age 46 years, 89 male). FIELD STRENGTH/SEQUENCE: Time of flight, turbo inversion recovery magnitude T1WI, turbo spin echo (TSE) T2WI, echo-planar imaging DWI, T2-fluid attenuated inversion recovery, dynamic susceptibility contrast-magnetic resonance imaging, and pre- and post-contrast 3D TSE T1WI sequences at 3.0 Tesla. ASSESSMENT: Patients were assessed at baseline and followed yearly. Ischemic and hemorrhagic stroke incidence rates were determined. Multiple demographic, clinical (modified Rankin score [mRS]), and cerebral imaging (cerebral blood volume [CBV] and concentric enhancement of arterial wall) factors at baseline were considered as potential predictors of stroke during the follow-up period. STATISTICAL TESTS: Univariable and multivariable Cox proportional hazards models to calculate the hazard ratios (HRs) and corresponding 95% confidence interval (CI) for stroke. Cumulative risk of stroke was estimated by the Kaplan-Meier product-limit method. A P value <0.05 was considered statistically significant. RESULTS: The median follow-up duration was 47 months. During the follow-up period, 18 (11.25%) patients experienced stroke events (13 [8.13%] ischemic, 5 [3.12%] hemorrhagic). Univariable analysis showed that 11 factors were significantly associated with stroke. After adjustment for clinical characteristics, multivariable analysis showed that mRS score ≥3 (HR, 1.99; 95% CI, 1.26-3.14), decreased CBV (HR, 5.31; 95% CI, 2.32-12.13), and concentric enhancement of the arterial wall (HR, 4.16; 95% CI, 1.55-11.15) were significantly associated with stroke. DATA CONCLUSION: Decreased CBV, mRS score ≥ 3, and concentric enhancement of the arterial wall were significantly associated with increased incidence of stroke in conservatively treated MMD. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 4.
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Enfermedad de Moyamoya , Accidente Cerebrovascular , Humanos , Masculino , Persona de Mediana Edad , Estudios de Seguimiento , Enfermedad de Moyamoya/complicaciones , Enfermedad de Moyamoya/diagnóstico por imagen , Estudios Prospectivos , Estudios Retrospectivos , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/complicaciones , Imagen por Resonancia Magnética/métodosRESUMEN
Ionizing radiation (IR)-induced intestinal injury is usually accompanied by high lethality. Intestinal stem cells (ISCs) are critical and responsible for the regeneration of the damaged intestine. Astragalus polysaccharide (APS), one of the main active ingredients of Astragalus membranaceus (AM), has a variety of biological functions. This study was aimed to investigate the potential effects of APS on IR-induced intestine injury via promoting the regeneration of ISCs. We have established models of IR-induced intestinal injury and our results showed that APS played great radioprotective effects on the intestine. APS improved the survival rate of irradiated mice, reversed the radiation damage of intestinal tissue, increased the survival rate of intestinal crypts, the number of ISCs and the expression of intestinal tight junction-related proteins after IR. Moreover, APS promoted the cell viability while inhibited the apoptosis of MODE-K. Through organoid experiments, we found that APS promoted the regeneration of ISCs. Remarkably, the results of network pharmacology, RNA sequencing and RT-PCR assays showed that APS significantly upregulated the HIF-1 signalling pathway, and HIF-1 inhibitor destroyed the radioprotection of APS. Our findings suggested that APS promotes the regeneration of ISCs through HIF-1 signalling pathway, and it may be an effective radioprotective agent for IR-induced intestinal injury.
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Planta del Astrágalo , Transducción de Señal , Ratones , Animales , Polisacáridos/farmacología , Intestinos , Células MadreRESUMEN
BACKGROUND: The features of intracranial arteries in patients with Moyamoya disease (MMD) have been widely investigated. However, the MR characteristics of extracranial internal carotid artery (EICA) and their effect on outcomes of revascularization treatment are not fully understood. PURPOSE: To investigate the characteristics of EICA and their relationship with outcomes of revascularization treatment in adult patients with MMD based on higher-resolution MRI (HRMRI). STUDY TYPE: Prospective interventional outcomes. SUBJECTS: Two hundred eighty-eight consecutive patients with MMD (mean age: 43.7 ± 11.2 years; 140 male). FIELD STRENGTH/SEQUENCE: Turbo inversion recovery magnitude T1-weighted imaging and turbo spin echo (TSE) T2-weighted imaging, three-dimensional time-of-flight MR angiography, T2-fluid attenuated inversion recovery, and 3D T1-SPACE vessel wall imaging at 3.0 T. ASSESSMENT: The HRMRI characteristics of EICA were determined. The relationship between the characteristics of EICA (proximal stenosis, diffuse wall thickening, carotid plaques, and luminal thrombosis) and stroke outcomes of revascularization treatment in patients with MMD was analyzed. The discriminative ability of EICA characteristics in combination with intracranial carotid artery features (involvement of vessel segments, bilateral involvement, and Suzuki stage) to determine stroke outcomes was compared with that of intracranial artery features alone during a mean 8.0 months follow-up period. STATISTICAL TESTS: Cox proportional hazards models and Kaplan-Meier curves to calculate the hazard ratios (HRs) for stroke with 95% confidence intervals (CIs). Area under the receiver operating characteristic curve (AUC) for assessing discriminative performance. A P value <0.05 was considered statistically significant. RESULTS: During a mean 8.0 ± 2.2 months follow-up, of the 288 participants, 137 had proximal stenosis (47.6%), 106 had diffuse wall thickening (36.8%), 60 had carotid plaques (20.8%), and 27 had luminal thrombosis (9.4%) of EICA. Of these features, proximal stenosis (HR = 2.86; 95% CI = 1.13-7.29) and diffuse wall thickening (HR = 2.62; 95% CI = 1.16-5.94) of EICA were significantly associated with stroke after surgery, before and after adjusting for confounding factors. In discriminating the stroke outcomes after surgery, combining characteristics of EICA with features of intracranial arteries resulted in a significant incremental improvement (DeLong test, P < 0.05) in the AUC over that obtained with features of intracranial arteries alone (AUC: 0.73 vs. 0.60-0.64). CONCLUSION: Proximal stenosis and diffuse wall thickening of EICA were significantly associated with stroke outcomes after surgery in patients with MMD. Our findings suggest that understanding the characteristics of EICA has added value for intracranial vessels in predicting future events after surgery in patients with MMD. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 4.
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BACKGROUND: Neoadjuvant radiotherapy has been used as the standard treatment of colorectal cancer (CRC). However, radiotherapy resistance often results in treatment failure. To identify radioresistant genes will provide novel targets for combined treatments and prognostic markers. METHODS: Through high content screening and tissue array from CRC patients who are resistant or sensitive to radiotherapy, we identified a potent resistant gene SUMO specific peptidase 5 (SENP5). Then, the effect of SENP5 on radiosensitivity was investigated by CCK8, clone formation, comet assay, immunofluorescence and flow cytometric analysis of apoptosis and cell cycle to investigate the effect of SENP5 on radiosensitivity. SUMO-proteomic mass spectrometry combined with co-immunoprecipitation assay were used to identify the targets of SENP5. Patient-derived organoids (PDO) and xenograft (PDX) models were used to explore the possibility of clinical application. RESULTS: We identified SENP5 as a potent radioresistant gene through high content screening and CRC patients tissue array analysis. Patients with high SENP5 expression showed increased resistance to radiotherapy. In vitro and in vivo experiments demonstrated that SENP5 knockdown significantly increased radiosensitivity in CRC cells. SENP5 was further demonstrated essential for efficient DNA damage repair in homologous recombination (HR) dependent manner. Through SUMO mass spectrometry analysis, we characterized H2AZ as a deSUMOylation substrate of SENP5, and depicted the SUMOylation balance of H2AZ in HR repair and cancer resistance. By using PDO and PDX models, we found targeting SENP5 significantly increased the therapeutic efficacy of radiotherapy. CONCLUSION: Our findings revealed novel role of SENP5 in HR mediated DNA damage repair and cancer resistance, which could be applied as potent prognostic marker and intervention target for cancer radiotherapy.
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Neoplasias Colorrectales , Proteómica , Humanos , Reparación del ADN por Recombinación , Recombinación Homóloga , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/radioterapia , Daño del ADNRESUMEN
OBJECTIVE: The aim of the study is to demonstrate whether radiomics based on an automatic segmentation method is feasible for predicting molecular subtypes. METHODS: This retrospective study included 516 patients with confirmed breast cancer. An automatic segmentation-3-dimensional UNet-based Convolutional Neural Networks, trained on our in-house data set-was applied to segment the regions of interest. A set of 1316 radiomics features per region of interest was extracted. Eighteen cross-combination radiomics methods-with 6 feature selection methods and 3 classifiers-were used for model selection. Model classification performance was assessed using the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity. RESULTS: The average dice similarity coefficient value of the automatic segmentation was 0.89. The radiomics models were predictive of 4 molecular subtypes with the best average: AUC = 0.8623, accuracy = 0.6596, sensitivity = 0.6383, and specificity = 0.8775. For luminal versus nonluminal subtypes, AUC = 0.8788 (95% confidence interval [CI], 0.8505-0.9071), accuracy = 0.7756, sensitivity = 0.7973, and specificity = 0.7466. For human epidermal growth factor receptor 2 (HER2)-enriched versus non-HER2-enriched subtypes, AUC = 0.8676 (95% CI, 0.8370-0.8982), accuracy = 0.7737, sensitivity = 0.8859, and specificity = 0.7283. For triple-negative breast cancer versus non-triple-negative breast cancer subtypes, AUC = 0.9335 (95% CI, 0.9027-0.9643), accuracy = 0.9110, sensitivity = 0.4444, and specificity = 0.9865. CONCLUSIONS: Radiomics based on automatic segmentation of magnetic resonance imaging can predict breast cancer of 4 molecular subtypes noninvasively and is potentially applicable in large samples.
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Neoplasias de la Mama , Neoplasias de la Mama Triple Negativas , Humanos , Femenino , Neoplasias de la Mama/patología , Estudios Retrospectivos , Imagen por Resonancia Magnética/métodos , Neoplasias de la Mama Triple Negativas/patología , Curva ROC , Redes Neurales de la ComputaciónRESUMEN
BACKGROUND: Our previous study first showed that ATR-binding long noncoding RNA (lncRNA) is necessary for ATR function and promotes cancer resistance. However, the specific lncRNAs instrumental in ATR activation remain largely unclear, which limits our comprehensive understanding of this critical biological process. METHODS: RNA immunoprecipitation (RIP) followed by RNA sequencing was employed to identify ATR-binding lncRNAs, which were further validated using RIP-qPCR assays. Immunofluorescence staining and Western blotting were applied to detect the activation of DNA damage repair factors. After the effect of scaRNA2 on cellular sensitivity to DNA-damaging reagents was determined, the effects of scaRNA2 on radiotherapy were investigated in patient-derived organoids and xenograft preclinical models. The clinical relevance of scaRNA2 was also validated in tissues isolated from rectal cancer patients. RESULTS: ScaRNA2 was identified as the most enriched ATR-binding lncRNA and was found to be essential for homologous recombination (HR) mediated DNA damage repair. Furthermore, scaRNA2 knockdown abrogated the recruitment of ATR and its substrates in response to DNA damage. Mechanistically, scaRNA2 was observed to be necessary for Exo1-mediated DNA end resection and bridged the MRN complex to ATR activation. Knockdown of scaRNA2 effectively increased the sensitivity of cancer cells to multiple kinds of DNA damage-related chemoradiotherapy. Preclinically, knockdown of scaRNA2 improved the effects of radiotherapy on patient-derived organoids and xenograft models. Finally, an increase in scaRNA2 colocalized with ATR was also found in clinical patients who were resistant to radiotherapy. CONCLUSIONS: ScaRNA2 was identified as the most abundant lncRNA bound to ATR and was demonstrated to bridge DNA end resection to ATR activation; thus, it could be applied as a potent target for combined cancer treatments with chemoradiotherapy.
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Neoplasias , ARN Largo no Codificante , Humanos , Reparación del ADN por Recombinación , ARN Largo no Codificante/genética , Reparación del ADN , Daño del ADN , ADN , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteínas de la Ataxia Telangiectasia Mutada/metabolismoRESUMEN
BACKGROUND: DNA-damaging agents, including radiation and platinum-based chemotherapy, are indispensable treatments for non-small cell lung cancer (NSCLC) patients. However, cancer cells tend to be resistant to both radiation and chemotherapy, thus resulting in treatment failure or recurrence. The purpose of this study was to explore the effect and mechanism of long non-coding RNA (lncRNA) PANDAR (promoter of CDKN1A antisense DNA damage-activated RNA) on NSCLC sensitivity to radiation and chemotherapy. METHODS: Cell counting kit (CCK-8), colony formation and flow cytometry were respectively performed to determine the cell cycle and apoptosis of NSCLC cells treated with γ-ray radiation and cisplatin. The extent of DNA damage was evaluated using a comet assay and immunofluorescence staining against γH2AX. In addition, we explored the role of PANDAR in DNA damage response pathways through western blot analysis. Finally, a nude mouse subcutaneous xenograft model was established to assess the sensitivity to radiation and chemotherapy in vivo. RESULTS: In cell experiments, PANDAR knockdown can increase the sensitivity of NSCLC cells to radiation and cisplatin. The CCK-8 results showed that cell viability was significantly increased in the overexpression group after radiation and cisplatin treatments. The overexpression group also showed more colonies, less apoptosis and DNA damage, and G2/M phase arrest was aggravated to provide the time necessary for DNA repair. Contrary to PANDAR overexpression, the trends were reversed in the PANDAR knockdown group. Furthermore, PANDAR knockdown inhibited radiation and cisplatin-activated phosphorylation levels of ATR and CHK1 in NSCLC cells. Finally, our in vivo model showed that targeting PANDAR significantly sensitized NSCLC to radiation and cisplatin. CONCLUSION: Our study showed that PANDAR knockdown promoted sensitivity to radiation and cisplatin in NSCLC by regulating the ATR/CHK1 pathway, thus providing a novel understanding as well as a therapeutic target for NSCLC treatment. In NSCLC cells, lncRNA PANDAR negatively regulates sensitivity to radiation and cisplatin. PANDAR can promote the repair of radiation and cisplatin-induced DNA damage and activation of the G2/M checkpoint through the ATR/CHK1 pathway. PANDAR knockdown results in defects in DNA damage repair accompanied by more cell apoptosis.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , ARN Largo no Codificante , Animales , Ratones , Humanos , Cisplatino/farmacología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/terapia , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/tratamiento farmacológico , Línea Celular Tumoral , Reparación del ADN/genética , Daño del ADN , Apoptosis/genética , Proliferación Celular/genética , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Proteínas de la Ataxia Telangiectasia Mutada/uso terapéuticoRESUMEN
OBJECTIVES: To evaluate the diagnostic performance of high-resolution magnetic resonance-vessel wall imaging (HRMR-VWI) in differentiating moyamoya disease (MMD) from atherosclerosis-associated moyamoya vasculopathy (AS-MMV) and investigate an accurate approach for the differential diagnosis. METHODS: Adult patients who were diagnosed as MMD or AS-MMV and underwent HRMR-VWI were retrospectively included. The three vessel wall features (outer diameter (OD), remodeling index (RI), and pattern of vessel wall thickening) of middle cerebral artery (MCA) in identifying MMD from AS-MMV were assessed and compared. Furthermore, subgroup analysis stratified by degree of luminal stenosis was performed and the cutoff values of different vessel wall features in differentiating MMD from AS-MMV were also calculated. RESULTS: A total of 265 patients (160 cases of MMD and 105 AS-MMV) were included. Patients with AS-MMV had greater OD and RI and were more likely to exhibit eccentric thickening of vessel wall compared to those with MMD (all p < 0.001). The ROC analysis showed that the AUC value of OD was greater than that of RI (0.912 vs. 0.889, p = 0.007) in differentiating MMD from AS-MMV, and their corresponding cutoff values were 1.77 mm and 0.27, respectively. And the AUC value of pattern of vessel wall thickening was 0.786 in non-occluded patients. With the increase of lumen stenosis, the discrimination power of the three indicators enhanced correspondingly. CONCLUSIONS: HRMR-VWI is valuable in distinguishing MMD from AS-MMV. The OD of MCA has better diagnostic performance in differentiating AS-MMV from MMD compared to RI and pattern of vessel wall thickening. CLINICAL RELEVANCE STATEMENT: The outer diameter of the involved artery proved to be both accurate and convenient in distinguishing atherosclerosis-associated moyamoya vasculopathy from moyamoya disease and may provide a quantitative reference for clinical diagnosis. KEY POINTS: High-resolution magnetic resonance-vessel wall imaging is valuable in distinguishing atherosclerosis-associated moyamoya vasculopathy from moyamoya disease. Compared to remodeling index and pattern of vessel wall thickening, outer diameter is more accurate in differentiating atherosclerosis-associated moyamoya vasculopathy from moyamoya disease. With the increase of lumen stenosis, the discrimination power of outer diameter, remodeling index, and pattern of vessel wall thickening enhanced correspondingly.
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Aterosclerosis , Enfermedad de Moyamoya , Adulto , Humanos , Enfermedad de Moyamoya/complicaciones , Enfermedad de Moyamoya/diagnóstico por imagen , Estudios Retrospectivos , Constricción Patológica , Imagen por Resonancia Magnética/métodos , Aterosclerosis/complicaciones , Aterosclerosis/diagnóstico por imagen , Arteria Cerebral Media , Espectroscopía de Resonancia Magnética , Angiografía por Resonancia Magnética/métodosRESUMEN
Surpassing the standard quantum limit and even reaching the Heisenberg limit using quantum entanglement, represents the Holy Grail of quantum metrology. However, quantum entanglement is a valuable resource that does not come without a price. The exceptional time overhead for the preparation of large-scale entangled states raises disconcerting concerns about whether the Heisenberg limit is fundamentally achievable. Here, we find a universal speed limit set by the Lieb-Robinson light cone for the quantum Fisher information growth to characterize the metrological potential of quantum resource states during their preparation. Our main result establishes a strong precision limit of quantum metrology accounting for the complexity of many-body quantum resource state preparation and reveals a fundamental constraint for reaching the Heisenberg limit in a generic many-body lattice system with bounded one-site energy. It enables us to identify the essential features of quantum many-body systems that are crucial for achieving the quantum advantage of quantum metrology, and brings an interesting connection between many-body quantum dynamics and quantum metrology.
RESUMEN
BACKGROUND: Long-term effects of human mesenchymal stem cell (MSC) treatment on COVID-19 patients have not been fully characterized. The aim of this study was to evaluate the safety and efficacy of a MSC treatment administered to severe COVID-19 patients enrolled in our previous randomized, double-blind, placebo-controlled clinical trial (NCT04288102). METHODS: A total of 100 patients experiencing severe COVID-19 received either MSC treatment (n = 65, 4 × 107 cells per infusion) or a placebo (n = 35) combined with standard of care on days 0, 3, and 6. Patients were subsequently evaluated 18 and 24 months after treatment to evaluate the long-term safety and efficacy of the MSC treatment. Outcomes measured included: 6-min walking distance (6-MWD), lung imaging, quality of life according to the Short Form 36 questionnaire (SF-36), COVID-19-related symptoms, titers of SARS-CoV-2 neutralizing antibodies, tumor markers, and MSC-related adverse events (AEs). FINDINGS: Two years after treatment, a marginally smaller proportion of patients had a 6-MWD below the lower limit of the normal range in the MSC group than in the placebo group (OR = 0.19, 95% CI: 0.04-0.80, Fisher's exact test, p = 0.015). At month 18, the general health score from the SF-36 was higher in the MSC group than in the placebo group (50.00 vs. 35.00, 95% CI: 0.00-20.00, Wilcoxon rank sum test, p = 0.018). Total severity score of lung imaging and the titer of neutralizing antibodies were similar between the two groups at months 18 and 24. There was no difference in AEs or tumor markers at the 2-year follow-up between the two groups. INTERPRETATION: Long-term safety was observed for the COVID-19 patients who received MSC treatment. However, efficacy of MSC treatment was not significantly sustained through the end of the 2-year follow-up period. FUNDING: The National Key Research and Development Program of China (2022YFA1105604, 2020YFC0860900, 2022YFC2304401), the specific research fund of The Innovation Platform for Academicians of Hainan Province (YSPTZX202216) and the Fund of National Clinical Center for Infectious Diseases, PLA General Hospital (NCRC-ID202105,413FZT6).