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Histone methylation is a key epigenetic modification that regulates the chromatin structure and gene expression for proper cellular and physiological processes. Aberrant histone methylation patterns are implicated in many diseases. Therefore, monitoring histone methylation dynamics in living cells and species is essential for elucidating its regulatory mechanisms and identifying potential therapeutic targets. However, current methods for detecting histone methylation are limited by their low sensitivity and specificity. To overcome this challenge, we have developed a genetically encoded biosensor named Phaser-Trim (Phase separation based genetically encoded reporter for H3K9 Trimethylation) to detect the dynamic changes of H3K9me3 in living cells and species through the generation and disappearance of phase-separated droplets. Phaser-Trim demonstrates advantages of clear phenotypic characteristics, convenient operation, quantitative accuracy, biocompatibility, high specificity, and superior imaging performance with high signal-to-background ratio (SBR) for in vivo animal imaging. Using Phaser-Trim, we have successfully detected the dynamics of the H3K9me3 level during the differentiation of neural stem cells in Drosophila. Furthermore, Phaser-Trim also holds promise for application in high-throughput screening systems to facilitate the discovery of novel anticancer drugs.
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Histonas , Histonas/metabolismo , Histonas/química , Animales , Metilación , Humanos , Técnicas Biosensibles/métodos , Células-Madre Neurales/metabolismo , Células-Madre Neurales/citología , Drosophila , Diferenciación Celular , Separación de FasesRESUMEN
Lung cancer remains the leading cause of mortality worldwide. Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer with a generally poor prognosis. In recent years, advances in targeted therapy and sequencing technology have brought significant improvement in the therapeutic outcomes of patients with advanced NSCLC. Targeted inhibitors directed against specific mutated or rearranged oncogenes, such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and receptor tyrosine kinase ROS proto-oncogene 1(ROS1) among others, exhibit promising anti-tumor activity. Unfortunately, some patients develop acquired resistance and disease progression soon after initial remission. Despite the continuous development of new drugs and strategies to overcome drug resistance, it is still a major challenge in the treatment of NSCLC. The landscape of targeted therapy for NSCLC is evolving rapidly in response to the pace of scientific research. This study aimed to provide a comprehensive review of tumor target antigens and agents related to targeted therapy in NSCLC.
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Bats are the natural reservoir hosts for SARS-related coronavirus (SARSr-CoV) and other highly pathogenic microorganisms. Therefore, it is conceivable that an individual bat may harbor multiple microbes. However, there is limited knowledge on the overall co-circulation of microorganisms in bats. Here, we conducted a 16-year monitoring of bat viruses in south and central China and identified 238 SARSr-CoV positive samples across nine bat species from ten provinces or administrative districts. Among these, 76 individual samples were selected for further metagenomics analysis. We found a complex microenvironment characterized by the general co-circulation of microbes from two different sources: mammal-associated viruses or environment-associated microbes. The later includes commensal bacteria, enterobacteria-related phages, and insect or fungal viruses of food origin. Results showed that 25% (19/76) of the samples contained at least one another mammal-associated virus, notably alphacoronaviruses (13/76) such as AlphaCoV/YN2012, HKU2-related CoV and AlphaCoV/Rf-HuB2013, along with viruses from other families. Notably, we observed three viruses co-circulating within a single bat, comprising two coronavirus species and one picornavirus. Our analysis also revealed the potential presence of pathogenic bacteria or fungi in bats. Furthermore, we obtained 25 viral genomes from the 76 bat SARSr-CoV positive samples, some of which formed new evolutionary lineages. Collectively, our study reveals the complex microenvironment of bat microbiome, facilitating deeper investigations into their pathogenic potential and the likelihood of cross-species transmission.
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Quirópteros , Coinfección , Metagenómica , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo , Viroma , Quirópteros/virología , Animales , China , Coinfección/virología , Coinfección/veterinaria , Coinfección/microbiología , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/genética , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/aislamiento & purificación , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/clasificación , Filogenia , Genoma Viral/genética , Reservorios de Enfermedades/virologíaRESUMEN
Background: The development of tyrosine kinase inhibitor (TKI) therapy has positively impacted the survival rates of patients with chronic myeloid leukemia (CML). It is common in medical practice to adjust the dosage of TKI downward because of TKI-associated adverse events, financial burden, comorbidity, or an attempt at treatment-free remission. Objectives: This investigation sought to explore the feasibility of employing a reduced dosage of TKI for treating CML. Design: This was a retrospective study. Methods: Patients with CML in its chronic phase who had been on a reduced dose of TKI for a minimum of 3 months for various reasons in a practical clinical environment, irrespective of molecular response, were included. Regular molecular monitoring was performed, and changes in adverse events were recorded after dose reduction. Results: This research included a total of 144 participants. Upon reducing the dosage, 136 of 144 patients achieved major molecular response or deeper, and 132 of 144 achieved molecular response 4 (MR4). Following a median observation period of 16 months, the calculated 1- and 2-year survival rates free from MR4 failure were estimated to be 96.5% (95% CI: 90.8-98.7) and 90.5% (95% CI: 81.3-95.3), respectively. MR4 failure-free survival was better in patients with longer MR4 durations (⩾34 months) before dose reduction (p = 0.02). The median interval from dose reduction to MR4 loss was 15 months. Improved TKI-associated adverse events after dose reduction were observed in 61.3% of patients. Conclusion: Lowering the TKI dose can effectively preserve a deep molecular response over time while relieving adverse events caused by TKIs.
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OBJECTIVE: This study aimed to develop and validate a prenatal nomogram to predict the risk of placenta accreta spectrum (PAS) in women with one previous cesarean delivery. METHODS: This retrospective study enrolled 5157 pregnant women with one previous cesarean delivery in China from January 2021 to January 2023. The nomogram was developed from a training cohort of 3612 pregnant women and tested on a validation cohort of 1545 pregnant women. Multivariate regression analysis was performed using the minimum value of the Akaike information criterion to select prognostic factors that can be included in the nomogram. We evaluated the nomogram by the area under the receiver operating characteristic (ROC) curve, calibration curves, and the decision curve analysis (DCA). RESULTS: PAS occurred in 199 (5.51%) and 80 (5.18%) patients in the training and validation cohorts, respectively. Backward stepwise algorithms in the multivariable logistic regression model determined abortion, hypertensive disorders complicating pregnancy, fetal position, and placenta previa as relevant PAS predictors. The area under the ROC curve for the nomogram was 0.770 (95% confidence interval [CI] 0.733-0.807) and 0.791 (95% CI 0.730-0.853) for the training and validation cohorts, respectively. The calibration curves indicated that the nomogram's prediction probability was consistent with the actual probability. The DCA curve revealed that the nomogram has potential clinical benefit. CONCLUSION: A prenatal nomogram was developed for PAS in our study, which helped obstetricians determine potential patients with PAS and make sufficient preoperative preparation to reduce maternal and neonatal complications.
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Low-coverage whole-genome sequencing (LCS) offers a cost-effective alternative for sturgeon breeding, especially given the lack of SNP chips and the high costs associated with whole-genome sequencing. In this study, the efficiency of LCS for genotype imputation and genomic prediction was assessed in 643 sequenced Russian sturgeons (â¼13.68×). The results showed that using BaseVar+STITCH at a sequencing depth of 2× with a sample size larger than 300 resulted in the highest genotyping accuracy. In addition, when the sequencing depth reached 0.5× and SNP density was reduced to 50 K through linkage disequilibrium pruning, the prediction accuracy was comparable to that of whole sequencing depth. Furthermore, an incremental feature selection method has the potential to improve prediction accuracy. This study suggests that the combination of LCS and imputation can be a cost-effective strategy, contributing to the genetic improvement of economic traits and promoting genetic gains in aquaculture species.
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Peces , Polimorfismo de Nucleótido Simple , Peces/genética , Animales , Secuenciación Completa del Genoma/economía , Secuenciación Completa del Genoma/métodos , Genómica/métodos , Genómica/economía , Análisis Costo-Beneficio , Desequilibrio de LigamientoRESUMEN
BACKGROUND: The incidence of gastric cancer has significantly increased in recent years. Surgical resection is the main treatment, but the method of digestive tract reconstruction after gastric cancer surgery remains controversial. In the current study, we sought to explore a reasonable method of digestive tract reconstruction and improve the quality of life and nutritional status of patients after surgery. To this end, we statistically analyzed the clinical results of patients with gastric cancer who underwent jejunal interposition double-tract reconstruction (DTR) and esophageal jejunum Roux-en-Y reconstruction (RY). AIM: To explore the application effect of DTR in total laparoscopic radical total gastrectomy (TLTG) and evaluate its safety and efficacy. METHODS: We collected the relevant data of 77 patients who underwent TLTG at the Fourth Hospital of Hebei Medical University from October 2021 to January 2023. Among them, 35 cases were treated with DTR, and the remaining 42 cases were treated with traditional RY. After 1:1 propensity score matching, the cases were grouped into 31 cases per group, with evenly distributed data. The clinical characteristics and short- and long-term clinical outcomes of the two groups were statistically analyzed. RESULTS: The two groups showed no significant differences in basic data, intraoperative blood loss, number of lymph node dissections, first defecation time after operation, postoperative hospital stay, postoperative complications, and laboratory examination results on the 1st, 3rd, and 5th days after operation. The operation time of the DTR group was longer than that of the RY group [(307.58 ± 65.14) min vs (272.45 ± 62.09) min, P = 0.016], but the first intake of liquid food in the DTR group was shorter than that in the RY group [(4.45 ± 1.18) d vs (6.0 ± 5.18) d, P = 0.028]. The incidence of reflux heartburn (Visick grade) and postoperative gallbladder disease in the DTR group was lower than that in the RY group (P = 0.033 and P = 0.038). Although there was no significant difference in body weight, hemoglobin, prealbumin, and albumin between the two groups at 1,3 and 6 months after surgery, the diet of patients in the DTR group was better than that in the RY group (P = 0.031). CONCLUSION: The clinical effect of DTR in TLTG is better than that of RY, indicating that it is a more valuable digestive tract reconstruction method in laparoscopic gastric cancer surgery.
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Lymphoma and leukemia are both hematological system tumors with complex etiology, and mainly treated with chemotherapeutic drugs. However, therapeutic drugs can interrupt curative effect due to different side effects. Therefore, it is worthwhile to develop a novel therapeutic for providing insights for clinical tumor treatment. In this study, we developed a fisetin nanoparticles (Fisetin NPs) through a self-assembled method, and investigated the activity and potential mechanism of Fisetin NPs against lymphoma and leukemia. The spherical and uniformly distributed Fisetin NPs effectively inhibited both tumor cells proliferation, arrested EL4 cells G0/G1 phase and K562 cells G2/M phase, and induced apoptosis in vitro. In vivo, Fisetin NPs exhibited excellent tumor growth inhibition, effective inhibition of cell proliferation and angiogenesis, significant induction of apoptosis and ideal safety. Mechanically, fisetin upregulated genes (Fas, Pidd, Puma, Apaf1, and p21) in the p53 signaling pathway and bound to N-acetyltransferase 10 (NAT10), ribosomal protein L34 (RPL34) and GTP binding protein 4 (GTPBP4). Collectively, Fisetin NPs have promising therapeutic effects on lymphoma and leukemia, which are of great significant for clinical implications.
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Leucemia , Linfoma , Humanos , Flavonoides/farmacología , Flavonoles/farmacología , Apoptosis , Proliferación Celular , Leucemia/tratamiento farmacológico , Linfoma/tratamiento farmacológico , Línea Celular Tumoral , Proteínas Nucleares/farmacología , Proteínas de Unión al GTP/farmacología , Acetiltransferasas N-TerminalRESUMEN
The preservation and advancement of Traditional Villages are intricately linked to the perpetuation of cultural heritage. However, existing research on the spatial disparities among Traditional Villages has yet to consider the impact of cultural factors. Moreover, the geographical similarities shared by Traditional Villages have not been thoroughly examined. Therefore, this study takes the Yellow River Basin and the Yangtze River Basin, both pivotal in the genesis of Chinese culture, as case studies. We employ an Optimal Parameter-based GeoDetector alongside the Spatially Constrained Multivariate Clustering method to delve into the factors influencing the spatial differentiation and geographical similarities of Traditional Villages within these two significant river basins. Subsequently, we offer recommendations for fostering the sustainable preservation and development of Traditional Villages in these regions. The results indicate that the Rural Residents Per Capita Disposable Income has the greatest impact on the spatial differentiation of Traditional Villages in the Yellow River Basin, while the Density of National Intangible Cultural Heritage Inheritors has the most significant influence in the Yangtze River Basin. The interaction effects of the driving factors are more powerful, with a q-value of 0.9544 for the interplay between the Density of National Cultural Protection Units and the Tourism Income in the Yellow River Basin and a value of 0.9099 for the interaction between the Density of National Intangible Cultural Heritage Inheritors and the Transportation in the Yangtze River Basin. Regarding geographical similarity, the Traditional Villages in the Yellow River Basin are divided into three major clusters, while those in the Yangtze River Basin are divided into two.
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High entropy materials offer almost unlimited catalytic possibilities due to their variable composition, unique structure, and excellent electrocatalytic performance. However, due to the strong tendency of nanoparticles to coarsen and agglomerate, it is still a challenge to synthesize nanoparticles using simple methods to precisely control the morphology and size of the nanoparticles in large quantities, and their large-scale application is limited by high costs and low yields. Herein, a series of high-entropy oxides (HEOs) nanoparticles with high-density and ultrasmall size (<5 nm) loaded on carbon nanosheets with large quantities are prepared by Joule-heating treatment of gel precursors in a short period of time (≈60 s). Among them, the prepared (FeCoNiRuMn)3O4-x catalyst shows the best electrocatalytic activity for oxygen evolution reaction, with low overpotentials (230 mV @10 mA cm-2, 270 mV @100 mA cm-2), small Tafel slope (39.4 mV dec-1), and excellent stability without significant decay at 100 mA cm-2 after 100 h. The excellent performance of (FeCoNiRuMn)3O4-x can be attributed to the synergistic effect of multiple elements and the inherent structural stability of high entropy systems. This study provides a more comprehensive design idea for the preparation of efficient and stable high entropy catalysts.
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With the optimization of surgical technologies and postoperative management regimens, the number of lung transplantation has been significantly increased, which has become an important treatment for patients with end-stage lung disease. However, due to the impact of comprehensive factors, such as bronchial ischemia and immunosuppression, the incidence of airway stenosis after lung transplantation is relatively high, which severely affects postoperative survival and quality of life of lung transplant recipients. In recent years, with the improvement of perioperative management, organ preservation and surgical technologies, the incidence of airway stenosis after lung transplantation has been declined, but it remains at a high level. Early diagnosis and timely intervention play a significant role in enhancing clinical prognosis of patients with airway stenosis. In this article, the general conditions, diagnosis, treatment and prevention of airway stenosis after lung transplantation were reviewed, aiming to provide reference for comprehensive management of airway stenosis after lung transplantation and improving clinical prognosis of lung transplant recipients.
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Objective To analyze the influencing factors of survival of patients with airway stenosis requiring clinical interventions after lung transplantation. Methods Clinical data of 66 patients with airway stenosis requiring clinical interventions after lung transplantation were retrospectively analyzed. Univariate and multivariate Cox’s regression models were adopted to analyze the influencing factors of survival of all patients with airway stenosis and those with early airway stenosis. Kaplan-Meier method was used to calculate the overall survival and delineate the survival curve. Results For 66 patients with airway stenosis, the median airway stenosis-free time was 72 (52,102) d, 27% (18/66) for central airway stenosis and 73% (48/66) for distal airway stenosis. Postoperative mechanical ventilation time [hazard ratio (HR) 1.037, 95% confidence interval (CI) 1.005-1.070, P=0.024] and type of surgery (HR 0.400, 95%CI 0.177-0.903, P=0.027) were correlated with the survival of patients with airway stenosis after lung transplantation. The longer the postoperative mechanical ventilation time, the higher the risk of mortality of the recipients. The overall survival of airway stenosis recipients undergoing bilateral lung transplantation was better than that of their counterparts after single lung transplantation. Subgroup analysis showed that grade 3 primary graft dysfunction (PGD) (HR 4.577, 95%CI 1.439-14.555, P=0.010) and immunosuppressive drugs (HR 0.079, 95%CI 0.022-0.287, P<0.001) were associated with the survival of patients with early airway stenosis after lung transplantation. The overall survival of patients with early airway stenosis after lung transplantation without grade 3 PGD was better compared with that of those with grade 3 PGD. The overall survival of patients with early airway stenosis after lung transplantation treated with tacrolimus was superior to that of their counterparts treated with cyclosporine. Conclusions Long postoperative mechanical ventilation time, single lung transplantation, grade 3 PGD and use of cyclosporine may affect the survival of patients with airway stenosis after lung transplantation.
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@#Objective To investigate the dietary patterns of rural residents in the high-incidence areas of esophageal cancer (EC), and to explore the clustering and influencing factors of risk factors associated with high-incidence characteristics. Methods A special structured questionnaire was applied to conduct a face-to-face survey on the dietary patterns of rural residents in Yanting county of Sichuan Province from July to August 2021. Univariate and multivariate logistic regression models were used to analyze the influencing factors of risk factor clustering for EC. Results There were 838 valid questionnaires in this study. A total of 90.8% of rural residents used clean water such as tap water. In the past one year, the people who ate fruits and vegetables, soybean products, onions and garlic in high frequency accounted for 69.5%, 32.8% and 74.5%, respectively; the people who ate kimchi, pickled vegetables, sauerkraut, barbecue, hot food and mildew food in low frequency accounted for 59.2%, 79.6%, 68.2%, 90.3%, 80.9% and 90.3%, respectively. The clustering of risk factors for EC was found in 73.3% of residents, and the aggregation of two risk factors was the most common mode (28.2%), among which tumor history and preserved food was the main clustering pattern (4.6%). The logistic regression model revealed that the gender, age, marital status and occupation were independent influencing factors for the risk factors clustering of EC (P<0.05). Conclusion A majority of rural residents in high-incidence areas of EC in Yanting county have good eating habits, but the clustering of some risk factors is still at a high level. Gender, age, marital status, and occupation are influencing factors of the risk factors clustering of EC.
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Background: The use of 5-hydroxytryptamine-3 receptor antagonists (5HT3RA) has long been considered the standard regimen for preventing chemotherapy-induced nausea and vomiting (CINV) prior to hematopoietic stem cell transplantation (HSCT). However, their therapeutic outcomes have been unsatisfactory. NEPA, an oral formulation combining the neurokinin-1 receptor antagonist netupitant and the 5HT3RA palonosetron, has received regulatory approval for the management of highly and moderately emetogenic chemotherapy. This study aims to compare the efficacy of NEPA with that of 5HT3RA alone in preventing CINV among patients undergoing multiday conditioning chemotherapy prior to HSCT. Patients and methods: We conducted a retrospective analysis of patients who underwent HSCT between September 2019 and September 2022. Efficacy outcomes were assessed based on the rates of patients achieving complete response (CR: no emesis and no use of rescue medication), complete control (CC: CR without significant nausea), no vomiting, and no significant nausea. Results: The NEPA group consisted of 106 patients, while the 5HT3RA group included 107 patients. The NEPA group exhibited significantly higher rates of CR compared to the 5HT3RA group during the overall phase (71.7% vs. 32.7%, P<0.001), acute phase (78.3% vs. 43.0%, P<0.001), and delayed phase (84.9% vs. 58.9%, P<0.001). Similarly, rates of CC, no vomiting, and no significant nausea were significantly better in the NEPA group across all phases (P<0.001). Conclusion: NEPA demonstrated superior efficacy compared to 5HT3RA in preventing CINV during all phases of multiday conditioning regimens among patients undergoing HSCT.
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PURPOSE: To develop and validate a model based on MRI radiomics modals for predicting surgical high FIGO(IB3 andâ¯≥â¯IIA2) and low FIGO(IB1, IB2, and IIA1) stages in patients with cervical carcinoma (CC) . METHODS: A total of 296 early-stage patients with CC (preoperative FIGO stages IB-IIA) confirmed by surgery and pathology were included in this retrospective study from two institutions For each patient,we extracted radiomics features from spectral attenuated inversion-recovery T2-weighted (SPAIR-T2W) and contrast-enhanced T1-weighted (CE-T1W) images.Manual segmentation was performed using the 3D Slicer software, while radiomics features were extracted, screened using the R software. A 2-stage feature extraction strategy involving univariate analysis and the Least Absolute Shrinkage Selection Operator technique was performed. A support vector machine-based model was eventually constructed. Predictive accuracy of the training and validation datasets was assessed in terms of area under the ROC curve (AUC). RESULTS: A total of 1130 features were extracted from SPAIR-T2WI and CET1WI images respectively, in which 8 and 7 features significantly were associated with FIGO staging. AUCs of the SPAIR-T2W and CE-T1W models were were 0.803 and 0.790, respectively, in the internal validation group. In the external validation group, the AUCs were 0.767 and 0.749, respectively, which increased to 0.771 in the combined model. CONCLUSION: Our study demonstrated the feasibility of radiomics features from SPAIR-T2W and CE-T1W images for the prediction of surgical FIGO stage in CC. Our proposed model thereby carries the potential as a non-invasive tool for the staging and treatment planning of this disease. ADVANCES IN KNOWLEDGE: A radiomics model provide a non-invasive and objective method for the detection of FIGO staging in patients with cervical cancer before surgery, thus providing a reference for the selection of treatment options for patients.
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Ankylosing spondylitis (AS) is a progressively worsening and disabling form of arthritis that primarily affects the axial skeleton. This disease mainly involves the spine and the sacroiliac joint. Fusion of the spine and the sacroiliac joint may occur in the later stage of the disease, resulting in spinal stiffness and kyphosis, as well as difficulty in walking, which seriously affects the quality of work and daily living activities and imposes a heavy burden on the patient, the family, and society. Increasing attention has been paid to non-pharmacotherapy as an alternative therapy for AS. Moxibustion is an ancient therapeutic technique used in Traditional Chinese Medicine (TCM). Du-moxibustion therapy, a unique and innovative external treatment developed on the basis of ordinary moxibustion, has a definite therapeutic effect on AS. Du-moxibustion skillfully combines the compatible techniques of TCM to integrate meridians, acupoints, Chinese herbal medicine, and moxibustion. This paper describes the operation procedures and precautions to be taken during Du-moxibustion in experimental mice in detail to provide an experimental basis for the study of the mechanism of Du-moxibustion in the treatment of AS.
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Terapia por Acupuntura , Meridianos , Moxibustión , Espondilitis Anquilosante , Humanos , Animales , Ratones , Moxibustión/métodos , Espondilitis Anquilosante/terapia , Medicina Tradicional ChinaRESUMEN
Bruchophagus huonchili is a pest that poses a serious threat to the yield and quality of Astragalus membranaceus seeds. In this study, we employed solid-phase microextraction (SPME) and gas chromatography-mass spectrometry (GC-MS) to identify volatile organic compounds (VOCs) in A. membranaceus pods during the pod-filled period. Additionally, we utilized a Y-tube olfactometer to measure the behavioral response of B. huonchili to different individual VOCs and specific VOC-based formulations. The most effective formulations were further evaluated for their effectiveness in attracting wasps in the field. Our findings revealed that A. membranaceus pods emit 25 VOCs, including green leaf volatiles (GLVs) and terpenoid and aromatic compounds. Among these compounds, five were found to be most attractive to B. huonchili at the following concentrations: 10 µg/µL cis-ß-ocimene, 500 µg/µL hexyl acetate, 100 µg/µL hexanal, 1 µg/µL decanal, and 10 µg/µL ß-caryophyllene, with respective response rates of 67.65%, 67.74%, 65.12%, 67.57%, and 66.67%. In addition, we evaluated 26 mixed VOC formulations, and three of them were effective at attracting B. huonchili. Furthermore, field experiments showed that one of the formulations was significantly more effective than the others, which could be used for monitoring B. huonchili populations.
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Natural killer (NK) cell based immunotherapy is an emerging strategy in hematologic malignancies because allogeneic NK cells can provide potent antitumor immunity without inducing graft-versus-host disease. Thus, we expanded cord blood-derived NK (CB-NK) cells ex vivo from random (MHC mismatched and KIR mismatched) donors, and investigate the feasibility and efficacy of repeated infusions CB-NK cells as maintenance therapy after autologous hematopoietic stem cell transplantation (ASCT). Thirty-one patients with acute myeloid leukemia and high-risk lymphoma received ASCT and the adoptive CB-NK cell multiple infusions for maintenance therapy. Patients received a median dose of 5.98 × 107/kg (range, 1.87-17.69 × 107/kg) CB-NK cells and 23 patients completed four infusions, 8 patients received three infusions. Only mild infusion reactions occurred in 15.5% of 116 infusions. Compared to a contemporaneous cohort of 90 patients who did not receive NK cell therapy, the adoptive transfer of CB-NK cells as maintenance treatment showed a tendency of difference in decreasing the relapse rate between CB-NK group and control group (9.7% vs 24.4%). The patients who receiving NK cell infusions had a better PFS and OS than controls (4 year PFS, 84.4 ± 8.3% vs 73.5 ± 5.4%; and 4 year OS, 100% vs 78.1 ± 5.4%) . These findings demonstrate safety and validity of maintenance therapy using CB-NK cells multiple infusions after ASCT, and it is worthy of further clinical trial verification.
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Sangre Fetal , Trasplante de Células Madre Hematopoyéticas , Humanos , Proyectos Piloto , Células Asesinas Naturales , Trasplante AutólogoRESUMEN
While the spike proteins from severe acute respiratory syndrome coronaviruses-1 and 2 (SARS-CoV and SARS-CoV-2) bind to host angiotensin-converting enzyme 2 (ACE2) to infect cells, the majority of bat sarbecoviruses cannot use ACE2 from any species. Despite their discovery almost 20 years ago, ACE2-independent sarbecoviruses have never been isolated from field samples, leading to the assumption these viruses pose little risk to humans. We have previously shown how spike proteins from a small group of ACE2-independent bat sarbecoviruses may possess the ability to infect human cells in the presence of exogenous trypsin. Here, we adapted our earlier findings into a virus isolation protocol and recovered two new ACE2-dependent viruses, RsYN2012 and RsYN2016A, as well as an ACE2-independent virus, RsHuB2019A. Although our stocks of RsHuB2019A rapidly acquired a tissue-culture adaption that rendered the spike protein resistant to trypsin, trypsin was still required for viral entry, suggesting limitations on the exogenous entry factors that support bat sarbecoviruses. Electron microscopy revealed that ACE2-independent sarbecoviruses have a prominent spike corona and share similar morphology to other coronaviruses. Our findings demonstrate a broader zoonotic threat posed by sarbecoviruses and shed light on the intricacies of coronavirus isolation and propagation in vitro. IMPORTANCE Several coronaviruses have been transmitted from animals to people, and 20 years of virus discovery studies have uncovered thousands of new coronavirus sequences in nature. Most of the animal-derived sarbecoviruses have never been isolated in culture due to cell incompatibilities and a poor understanding of the in vitro requirements for their propagation. Here, we built on our growing body of work characterizing viral entry mechanisms of bat sarbecoviruses in human cells and have developed a virus isolation protocol that allows for the exploration of these understudied viruses. Our protocol is robust and practical, leading to successful isolation of more sarbecoviruses than previous approaches and from field samples that had been collected over a 10-year longitudinal study.
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Enzima Convertidora de Angiotensina 2 , Betacoronavirus , Quirópteros , Receptores Virales , Animales , Humanos , Enzima Convertidora de Angiotensina 2/metabolismo , Quirópteros/virología , Pueblos del Este de Asia , Estudios Longitudinales , Receptores Virales/metabolismo , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/metabolismo , Tripsina , Betacoronavirus/aislamiento & purificación , ZoonosisRESUMEN
Bats carry genetically diverse severe acute respiratory syndrome-related coronaviruses (SARSr-CoVs). Some of them utilize human angiotensin-converting enzyme 2 (hACE2) as a receptor and cannot efficiently replicate in wild-type mice. Our previous study demonstrated that the bat SARSr-CoV rRsSHC014S induces respiratory infection and lung damage in hACE2 transgenic mice but not wild-type mice. In this study, we generated a mouse-adapted strain of rRsSHC014S, which we named SMA1901, by serial passaging of wild-type virus in BALB/c mice. SMA1901 showed increased infectivity in mouse lungs and induced interstitial lung pneumonia in both young and aged mice after intranasal inoculation. Genome sequencing revealed mutations in not only the spike protein but the whole genome, which may be responsible for the enhanced pathogenicity of SMA1901 in wild-type BALB/c mice. SMA1901 induced age-related mortality similar to that observed in SARS and COVID-19. Drug testing using antibodies and antiviral molecules indicated that this mouse-adapted virus strain can be used to test prophylactic and therapeutic drug candidates against SARSr-CoVs. IMPORTANCE The genetic diversity of SARSr-CoVs in wildlife and their potential risk of cross-species infection highlights the importance of developing a powerful animal model to evaluate the antibodies and antiviral drugs. We acquired the mouse-adapted strain of a bat-origin coronavirus named SMA1901 by natural serial passaging of rRsSHC014S in BALB/c mice. The SMA1901 infection caused interstitial pneumonia and inflammatory immune responses in both young and aged BALB/c mice after intranasal inoculation. Our model exhibited age-related mortality similar to SARS and COVID-19. Therefore, our model will be of high value for investigating the pathogenesis of bat SARSr-CoVs and could serve as a prospective test platform for prophylactic and therapeutic candidates.