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PURPOSE: To determine the impact of PM2.5 exposure in old age and its interactive effect with smoking on incident diabetes. METHODS: A total of 2766 participants aged ≥60â¯years in China were interviewed at baseline for disease risk factors in 2001-03 and were then followed up for 10â¯years to document incident diabetes. They were assessed for daily PM2.5 exposure in 2005. Multivariate Cox regression models were used to examine the association of PM2.5 exposure with incident diabetes and interactive effect between PM2.5 and smoking on incident diabetes. RESULTS: During the cohort follow-up, 176 participants developed diabetes. The incidence of diabetes increased with PM2.5 exposure; the multiple-adjusted hazard ratio (HR) of diabetes was 2.27 (95â¯% CI 1.36-3.77) in participants with PM2.5 at ≥62.0⯵g/m3 compared to those with <62.0⯵g/m3. There was a significant interaction effect of PM2.5 with smoking on increased risk of diabetes. The adjusted HR for participants exposed to PM2.5 levels ≥62.0⯵g/m3 who smoked was 4.39 (95â¯% CI 1.72-11.21), while for non-smokers it was 1.65 (95â¯% CI 0.88-3.09), compared to those with <62.0⯵g/m3. CONCLUSIONS: Exposure to PM2.5 in old age was associated with an increased incidence of diabetes and smoking enhanced the impact of PM2.5 on diabetic risk. These findings underscore the urgent need for air quality improvement measures and smoking cessation programs to mitigate the risk of diabetes in aging populations.
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BACKGROUND: Femoral nerve block (FNB) is a prevalent method used for postoperative pain management after knee surgery; however, it decreases the strength of the quadriceps muscle and is not conducive to early recovery after surgery. Pectineus muscle plane (PMP) block involves the injection of a local anaesthetic into the fascial plane below the pectineus muscle, where it blocks the obturator and saphenous nerves. However, there is little evidence on the effectiveness of PMP block for analgesia after knee surgery. The aim of this trial is to assess whether PMP block can improve postoperative analgesia, promote early recovery and reduce the length of hospital stay. METHODS AND ANALYSIS: In this randomised controlled study, 46 patients will be randomly allocated into two groups: the PMP block group (n=23) and the FNB group (n=23). The primary outcome measures will include Visual Analog Scale scores for pain at rest and during movement at various time points following knee surgery. Secondary outcomes will include the degree of active flexion, straight leg raise test performance, get-out-of-bed test result, 20 m walk test result, total dose administered via patient-controlled analgesia infusion pumps, hospital stay duration, patient satisfaction and postoperative complications, such as pulmonary embolism and deep vein thrombosis.This study protocol adheres to rigorous standards for ethical conduct and patient safety. The findings from this trial are expected to contribute valuable insights to the optimisation of postoperative pain management strategies and the improvement of early recovery outcomes for patients who undergo knee surgery. ETHICS AND DISSEMINATION: This trial has been approved by the ethics committee of Zhejiang Hospital (2022(128K)) on 17 November 2022, and inpatients who meet the inclusion criteria and diagnostic requirements are eligible for this study. Any subsequent protocol and informed consent document amendments must be approved by the responsible ethics committee. All communications with the regulatory authorities and the ethics committee must be recorded. All recruited patients will be informed of the trial purposes and their duties within the trial before randomisation. Recruited patients can withdraw from the study at any time without providing any specific reason. The patient data will be stored in a separate, safe place, but that it may be reviewed by the relevant investigator. The results will be published in international peer-reviewed medical journals. TRIAL REGISTRATION NUMBER: http://www.chictr.org.cn, ID: ChiCTR2300076018. Registered on 21 September 2023.
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Nervo Femoral , Bloqueio Nervoso , Dor Pós-Operatória , Humanos , Bloqueio Nervoso/métodos , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/prevenção & controle , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição da Dor , Tempo de Internação , Adulto , Articulação do Joelho/cirurgia , Manejo da Dor/métodos , Masculino , Feminino , Anestésicos Locais/administração & dosagem , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: The aim of this study is to provide guidance for refining medication protocols, developing alternative strategies, and enhancing protection against herpesvirus infections in personalized clinical settings. METHODS: Adverse drug events (ADEs) data for anti-herpesvirus from the first quarter of 2004 to the fourth quarter of 2022 were collected from the FDA Adverse Event Reporting System (FAERS). Disproportionality analysis was performed using Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), and Bayesian Confidence Propagation Neural Network (BCPNN) methods for data mining. RESULTS: A total of 18,591, 24,206, 6,150, and 419 reports of ADEs associated with acyclovir (ACV), valacyclovir (VACV), ganciclovir (GCV), and famciclovir (FCV) were screened and extracted from the FAERS. In this study, the report summarized the high frequency and strong correlation of ADEs for the four drugs at the Preferred Term (PT) level. Additionally, the analysis also identified the relationship between ADEs and factors such as age, gender, and severity of outcome at the System Organ Class (SOC) level. CONCLUSION: The safety reports for the four-nucleoside analogue anti-herpesvirus drugs are diverse and interconnected. Dosing for patients with herpesvirus infections should be tailored to their specific conditions and the potential risk of disease.
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The active graphite felt (GF) catalytic layer was effectively synthesized through a wet ultrasonic impregnation-calcination method, modified with CB and PTFE, and implemented in a pioneering side-aeration electrochemical in-situ H2O2 reactor. The optimal mass ratio (CB: PTFE 1:4) for the modified cathode catalytic layer was determined using a single-factor method. Operating under optimum conditions of initial pH 5, 0.5 L/min air flow, and a current density of 9 mA/cm2, the system achieved a remarkable maximum H2O2 accumulation of 560 mg/L, with the H2O2 production capacity consistently exceeding 95 % over 6 usage cycles. The refined mesoporous structure and improved three-phase interface notably amplified oxygen transfer, utilization, and H2O2 yield. Side aeration led to an oxygen concentration near the cathode reaching 20 mg/L, representing a five-fold increase compared to the 3.95 mg/L achieved with conventional bottom aeration. In the final application, the reaction system exhibited efficacy in the degradation of landfill leachate concentrate. After a 60-minute reaction, complete removal of chroma was attained, and the TOC degradation rate surpassed 60 %, marking a sixfold improvement over the conventional system. These results underscore the substantial potential of the system in H2O2 synthesis and environmental remediation.
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Eletrodos , Peróxido de Hidrogênio , Poluentes Químicos da Água , Peróxido de Hidrogênio/química , Poluentes Químicos da Água/química , Técnicas Eletroquímicas/métodos , Catálise , Grafite/química , Oxigênio/químicaRESUMO
Liver cancer ranks third globally among causes of cancer-related deaths, posing a significant public health challenge. However, current treatments are inadequate, prompting a growing demand for novel, safe, and effective therapies. Natural products (NPs) have emerged as promising candidates in drug development due to their diverse biological activities, low toxicity, and minimal side effects. This paper begins by reviewing existing treatment methods and drugs for liver cancer. It then summarizes the therapeutic effects of NPs sourced from various origins on liver cancer. Finally, we analyze the potential mechanisms of NPs in treating liver cancer, including inhibition of angiogenesis, migration, and invasion; regulation of the cell cycle; induction of apoptosis, autophagy, pyroptosis, and ferroptosis; influence on tumor metabolism; immune regulation; regulation of intestinal function; and regulation of key signaling pathways. This systematic review aims to provide a comprehensive overview of NPs research in liver cancer treatment, offering a foundation for further development and application in pharmaceuticals and functional foods.
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Produtos Biológicos , Neoplasias Hepáticas , Humanos , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Apoptose/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Animais , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Autofagia/efeitos dos fármacosRESUMO
RATIONALE AND OBJECTIVES: The aim of this study was to develop a deep learning radiomics nomogram (DLRN) based on B-mode ultrasound (BMUS) and color doppler flow imaging (CDFI) images for preoperative assessment of lymphovascular invasion (LVI) status in invasive breast cancer (IBC). MATERIALS AND METHODS: In this multicenter, retrospective study, 832 pathologically confirmed IBC patients were recruited from eight hospitals. The samples were divided into training, internal test, and external test sets. Deep learning and handcrafted radiomics features reflecting tumor phenotypes on BMUS and CDFI images were extracted. The BMUS score and CDFI score were calculated after radiomics feature selection. Subsequently, a DLRN was developed based on the scores and independent clinic-ultrasonic risk variables. The performance of the DLRN was evaluated for calibration, discrimination, and clinical usefulness. RESULTS: The DLRN predicted the LVI with accuracy, achieving an area under the receiver operating characteristic curve of 0.93 (95% CI 0.90-0.95), 0.91 (95% CI 0.87-0.95), and 0.91 (95% CI 0.86-0.94) in the training, internal test, and external test sets, respectively, with good calibration. The DLRN demonstrated superior performance compared to the clinical model and single scores across all three sets (p < 0.05). Decision curve analysis and clinical impact curve confirmed the clinical utility of the model. Furthermore, significant enhancements in net reclassification improvement (NRI) and integrated discrimination improvement (IDI) indicated that the two scores could serve as highly valuable biomarkers for assessing LVI. CONCLUSION: The DLRN exhibited strong predictive value for LVI in IBC, providing valuable information for individualized treatment decisions.
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The taste and tenderness of meat are the main determinants of carcass quality in many countries. This study aimed to discuss the mechanisms of intramuscular fat deposition in grazing and house-breeding cattle. We performed transcriptome analysis to characterize messenger RNA and microRNA (miRNA) expression profiles. A total of 456 and 66 differentially expressed genes (DEGs) and differentially expressed (DE) miRNAs were identified in the adipose tissue of grazing and house-breeding cattle. Kyoto Encyclopedia of Genes and Genomes pathway analysis identified the association of DEGs with fatty acid metabolism, fatty acid degradation, peroxisome proliferator-activated receptors signaling pathway, adenosine monophosphate-activated protein kinase signaling pathway, adipocytokine signaling pathway, and the association of DE miRNAs with mitogen-activated protein kinase signaling pathway. Apolipoprotein L domain containing 1, pyruvate dehydrogenase kinase 4, and sphingosine-1-phosphate lyase 1 genes may be the key regulators of fat metabolism in grazing cattle. Finally, we found that miR-211 and miR-331-5p were negatively correlated with the elongation of very long-chain fatty acids protein 6 (ELOVL6), and miR-331-5p might be the new regulator involved in fat metabolism. The results indicated that ELOVL6 participated in various functions and pathways related to fat metabolism. Meanwhile, miR-331-5p, as a new regulator, might play an essential role in this process. Our findings laid a more in-depth and systematic research foundation for the formation mechanism and characteristics of adipose tissue in grazing cattle.
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Vascular endothelial cells play a critical role in maintaining the health of blood vessels, but dysfunction can lead to cardiovascular diseases. The impact of arsenite exposure on cardiovascular health is a significant concern due to its potential adverse effects. This study aims to explore how NBR1-mediated autophagy in vascular endothelial cells can protect against oxidative stress and apoptosis induced by arsenite. Initially, our observations revealed that arsenite exposure increased oxidative stress and triggered apoptotic cell death in human umbilical vein endothelial cells (HUVECs). However, treatment with the apoptosis inhibitor Z-VAD-FMK notably reduced arsenite-induced apoptosis. Additionally, arsenite activated the autophagy pathway and enhanced autophagic flux in HUVECs. Interestingly, inhibition of autophagy exacerbated arsenite-induced apoptotic cell death. Our findings also demonstrated the importance of autophagy receptor NBR1 in arsenite-induced cytotoxicity, as it facilitated the recruitment of caspase 8 to autophagosomes for degradation. The protective effect of NBR1 against arsenite-induced apoptosis was compromised when autophagy was inhibited using pharmacological inhibitors or through genetic knockdown of essential autophagy genes. Conversely, overexpression of NBR1 facilitated caspase 8 degradation and reduced apoptotic cell death in arsenite-treated HUVECs. In conclusion, our study highlights the vital role of NBR1-mediated autophagic degradation of caspase 8 in safeguarding vascular endothelial cells from arsenite-induced oxidative stress and apoptotic cell death. Targeting this pathway could offer a promising therapeutic approach to mitigate cardiovascular diseases associated with arsenite exposure.
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Apoptose , Arsenitos , Autofagia , Caspase 8 , Células Endoteliais da Veia Umbilical Humana , Estresse Oxidativo , Humanos , Arsenitos/toxicidade , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Caspase 8/metabolismo , Caspase 8/genética , Estresse Oxidativo/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteólise/efeitos dos fármacos , Células CultivadasRESUMO
This is a case report of a 6-year-old girl with relapsed B cell acute lymphoblastic leukemia in which adoptive cell therapy was applied successfully to treat refractory human parvovirus (HPV) B19 infection. Allogenic chimeric antigen receptor (CAR) T-cell therapy (bispecific CD19/CD22) was bridged to hematopoietic stem cell transplantation (HSCT) using a haploidentical paternal donor. However, HPV B19 DNAemia progressed and transfusion-related graft versus host disease occurred. After finding a third-party related donor with a better HLA match, haploidentical HPV B19-seropositive CD45RA+ depleted cells (16.5 × 106/kg) were administered and paternal TCRαß+ depleted stem cell were retransplanted. The HPV B19 DNAemia became negative within 1 week and the reticulocyte, neutrophil, hemoglobin, and platelet counts gradually normalized. The patient remained stable during the 1-year outpatient follow-up period. Thus, our case report highlights that persistent B19 infection can lead to pancytopenia, aplastic crisis, and graft rejection and TCRαß+ depleted haplo-HSCT is an effective means of hematopoiesis recovery. CD45RO memory T-cell therapy is the key to treating and preventing the development of refractory severe HPV B19 infection.
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Transplante de Células-Tronco Hematopoéticas , Infecções por Parvoviridae , Parvovirus B19 Humano , Receptores de Antígenos de Linfócitos T alfa-beta , Humanos , Feminino , Criança , Parvovirus B19 Humano/imunologia , Infecções por Parvoviridae/terapia , Infecções por Parvoviridae/imunologia , Antígenos Comuns de Leucócito/metabolismo , Imunoterapia Adotiva/métodos , Anemia Aplástica/terapia , Anemia Aplástica/imunologia , Doença Enxerto-Hospedeiro/terapia , Doença Enxerto-Hospedeiro/imunologia , Resultado do Tratamento , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologiaRESUMO
Juvenile myelomonocytic leukaemia (JMML) is a rare myeloproliferative neoplasm requiring haematopoietic stem cell transplantation (HSCT) for potential cure. Relapse poses a significant obstacle to JMML HSCT treatment, as the lack of effective minimal residual disease (MRD)-monitoring methods leads to delayed interventions. This retrospective study utilized the droplet digital PCR (ddPCR) technique, a highly sensitive nucleic acid detection and quantification technique, to monitor MRD in 32 JMML patients. The results demonstrated that ddPCR detected relapse manifestations earlier than traditional methods and uncovered molecular insights into JMML MRD dynamics. The findings emphasized a critical 1- to 3-month window post-HSCT for detecting molecular relapse, with 66.7% (8/12) of relapses occurring within this period. Slow MRD clearance post-HSCT was observed, as 65% (13/20) of non-relapse patients took over 6 months to achieve ddPCR-MRD negativity. Furthermore, bone marrow ddPCR-MRD levels at 1-month post-HSCT proved to be prognostically significant. Relapsed patients exhibited significantly elevated ddPCR-MRD levels at this time point (p = 0.026), with a cut-off of 0.465% effectively stratifying overall survival (p = 0.007), event-free survival (p = 0.035) and cumulative incidence of relapse (p = 0.035). In conclusion, this study underscored ddPCR's superiority in JMML MRD monitoring post-HSCT. It provided valuable insights into JMML MRD dynamics, offering guidance for the effective management of JMML.
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Transplante de Células-Tronco Hematopoéticas , Leucemia Mielomonocítica Juvenil , Neoplasia Residual , Reação em Cadeia da Polimerase , Humanos , Neoplasia Residual/diagnóstico , Masculino , Feminino , Reação em Cadeia da Polimerase/métodos , Leucemia Mielomonocítica Juvenil/terapia , Leucemia Mielomonocítica Juvenil/genética , Leucemia Mielomonocítica Juvenil/diagnóstico , Estudos Retrospectivos , Prognóstico , Pré-Escolar , Lactente , CriançaRESUMO
With the intensification of global economic competition, innovation has become one of the core elements of vigorous development in various regions. Improving the innovation ability of cross-regional central cities is the main factor influencing whether a region can achieve economic and social development. In this paper, an innovation primacy index system is designed according to the links of the innovation value chain, and the innovation advantages and empirical effects are comprehensively analyzed by using the point-to-point method, entropy weight method, gravity model and two-way fixed effect model. Based on the data of 8 cities in the core area of the Huaihai Economic Zone from 2010 to 2020 in China, Xuzhou's innovation primacy ranks first in the core area of the Huaihai Economic Zone, which accords with its status as the central city of the region. Its index has been rising, and its development trend is also good. However, the overall innovation ability of the core area of the Huaihai Economic Zone is unbalanced; the overall economic foundation is not solid enough. In terms of knowledge innovation, R&D innovation and industrial innovation, the industrialization level, around the activation of Xuzhou city vitality, enhances the Xuzhou innovation radiation drive, leading to a decrease in the Huaihai Economic Zone. Finally, some corresponding suggestions on innovation primacy have been proposed for the city of the Huaihai Economic Zone.
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Desenvolvimento Industrial , Urbanização , China , Cidades , Indústrias , Desenvolvimento EconômicoRESUMO
Hyperalgesia resulting from sleep deprivation (SD) poses a significant a global public health challenge with limited treatment options. The nucleus accumbens (NAc) plays a crucial role in the modulation of pain and sleep, with its activity regulated by two distinct types of medium spiny neurons (MSNs) expressing dopamine 1 or dopamine 2 (D1-or D2) receptors (referred to as D1-MSNs and D2-MSNs, respectively). However, the specific involvement of the NAc in SD-induced hyperalgesia remains uncertain. Cannabidiol (CBD), a nonpsychoactive phytocannabinoid, has demonstrated analgesic effects in clinical and preclinical studies. Nevertheless, its potency in addressing this particular issue remains to be determined. Here, we report that SD induced a pronounced pronociceptive effect attributed to the heightened intrinsic excitability of D2-MSNs within the NAc in Male C57BL/6N mice. CBD (30 mg/kg, i.p.) exhibited an anti-hyperalgesic effect. CBD significantly improved the thresholds for thermal and mechanical pain and increased wakefulness by reducing delta power. Additionally, CBD inhibited the intrinsic excitability of D2-MSNs both in vitro and in vivo. Bilateral microinjection of the selective D2 receptor antagonist raclopride into the NAc partially reversed the antinociceptive effect of CBD. Thus, these findings strongly suggested that SD activates NAc D2-MSNs, contributing heightened to pain sensitivity. CBD exhibits antinociceptive effects by activating D2R, thereby inhibiting the excitability of D2-MSNs and promoting wakefulness under SD conditions.
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Canabidiol , Camundongos , Animais , Masculino , Canabidiol/farmacologia , Canabidiol/uso terapêutico , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Privação do Sono/complicações , Privação do Sono/tratamento farmacológico , Dopamina/farmacologia , Camundongos Endogâmicos C57BL , Receptores de Dopamina D2/metabolismo , Núcleo Accumbens , Dor , Receptores de Dopamina D1/metabolismo , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Camundongos TransgênicosRESUMO
Adipose tissue is a crucial economically significant trait that significantly influences the meat quality and growth performance of domestic animals. To reveal the changes in adipose tissue metabolism during the growth of naturally grazing sheep, we evaluated the thickness, adipocyte morphology, fatty acid profile, and metabolite profile of subcutaneous adipose tissue (SAT) from naturally grazing Sunit sheep at 6, 18, and 30 months of age (referred to as Mth-6, Mth-18, and Mth-30, respectively). The fat thickness and adipocyte number were significantly increased with the growth of the sheep (p < 0.05), and the increase of which from Mth-18 to Mth-30 was less than that from Mth-6 to Mth-18. Additionally, the alpha-linolenic acid metabolism was enhanced and fatty acid (FA) elongation increased with growth. The metabolomic analysis revealed 76 differentially expressed metabolites (DEMs) in the SAT in different growth stages. Interestingly, we observed elongation of FAs in lipids correlated with sheep growth. Furthermore, the expression of acylcarnitines was downregulated, and fatty acid amides, aspartic acid, acetic acid and phosphocholine were upregulated in Mth-18 and Mth-30 compared to Mth-6. Altogether, the study found that the difference in SAT in Mth-6 was great compared to Mth-18 and Mth-30. An increase in fat deposition via adipocyte proliferation with the growth of the sheep in naturally grazing. The DEMs of acylcarnitines, fatty acid amides, aspartic acid, acetic acid, and phosphocholine emerged as potential key regulators of adipose tissue metabolism. These findings illustrate the variation in and metabolic mechanism of sheep adipose tissue development under natural grazing, thus providing valuable insights into improving the edible quality of sheep meat and developing the mutton sheep industry.
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OBJECTIVE: To systematically evaluate the perioperative effects of enhanced recovery after surgery (ERAS) protocol on anterior cervical spine surgery by means of meta-analysis. METHODS: According to the PRISMA guidelines, the article's search on the China National Knowledge Infrastructure (CNKI), Wanfang data resource system, VIP, PubMed database and Cochrane library was conducted to identify clinical studies investigating the effects of ERAS protocols on anterior cervical spine surgery. A quantitative meta-analysis was performed for the clinical outcomes extracted from the studies that met inclusion criteria. RESULTS: Of the 21 studies identified from the article search, 10 studies met inclusion criteria. The meta-analysis showed shorter length of stay (LOS) (MD = -2.16, 95% CI (-2.57, -1.75), P < 0.00001) and higher patient satisfaction for the ERAS protocols (OR = 3.13, 95% CI (1.97, 4.98), P < 0.00001). Furthermore, ERAS programs led to significant decreases in cost (MD = -0.81, 95% CI (-1.08, -0.53), P < 0.00001) and complication rates (OR = 0.15, 95% CI (0.08, 0.27), P < 0.00001), but no difference in 90-day readmission (OR = 0.63, 95% CI (0.30, 1.35), P = 0.24). CONCLUSIONS: The data of this study suggest that the implementation of ERAS protocol decreases LOS, cost and complications rates and improve satisfaction for the patients undergoing anterior cervical spine surgery. To support the practice use of ERAS in anterior cervical spine surgery further, controlled trials will be indispensable.
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Vértebras Cervicais , Recuperação Pós-Cirúrgica Melhorada , Humanos , Vértebras Cervicais/cirurgia , Tempo de Internação/estatística & dados numéricos , Doenças da Coluna Vertebral/cirurgia , Satisfação do PacienteRESUMO
MicroRNAs (miRNAs) are regarded as important regulators in skeletal muscle development. To reveal the regulatory roles of miRNAs and their target mRNAs underlying the skeletal muscle development of Wuranke sheep, we investigated the miRNA and mRNA expression profiles in the biceps femoris of these sheep at the fetal (3 months of gestation) and 3- and 15-month-old postnatal stages. Consequently, a total of 1195 miRNAs and 24,959 genes were identified. Furthermore, 474, 461, and 54 differentially expressed miRNAs (DEMs) and 6783, 7407, and 78 differentially expressed genes (DEGs) were detected among three comparative groups. Functional analysis demonstrated that the target mRNAs of the DEMs were enriched in multiple pathways related to muscle development. Moreover, the interactions among several predicted miRNA-mRNA pairs (oar-miR-133-HDAC1, oar-miR-1185-5p-MYH1/HADHA/OXCT1, and PC-5p-3703_578-INSR/ACTG1) that potentially affect skeletal muscle development were verified using dual-luciferase reporter assays. In this study, we identified the miRNA and mRNA differences in the skeletal muscle of Wuranke sheep at different developmental stages and revealed that a series of candidate miRNA-mRNA pairs may act as modulators of muscle development. These results will contribute to future studies on the function of miRNAs and their target mRNAs during skeletal muscle development in Wuranke sheep.
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MicroRNAs , Ovinos/genética , Animais , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Perfilação da Expressão Gênica , Músculo Esquelético/metabolismo , Desenvolvimento Muscular/genéticaRESUMO
Purpose: Burkitt lymphoma (BL) is the most common tumor of non-Hodgkin's lymphoma (NHL) in children, accounting for about 40% of cases. Although different combined short-course chemotherapies have achieved a good effect, refractory/relapsed BL has a poor prognosis with cure rates less than 30%. Chimeric antigen receptor T cell (CAR-T) therapy has developed rapidly in recent years and achieved excellent results in acute lymphoblastic leukemia (ALL). However, in some cases, there is a failure to produce autologous CAR-T cells because of T-cell dysfunction. In such cases, allogeneic CAR-T therapy has to be considered. Methods: A 17-year-old boy with stage II BL did not respond to extensive chemotherapy and sequential autologous CAR-T therapy. Lentiviral vectors containing anti-CD20-BB-ζ (20CAR) and anti-CD22-BB-ζ (22CAR) transgenes were used to modify the T cells from an HLA-identical matched unrelated donor. Flow cytometry was used to assess the cytokine analyses and CAR-T cell persistence in peripheral blood, enumerated by qPCR as copies per ug DNA. Informed consent for autologous/allogeneic CAR-T therapy was obtained from the patient and his legal guardian. Results: Unedited HLA-matched allogeneic CD20 and CD22 CAR-T cells were infused after lymphodepletion chemotherapy with cyclophosphamide and fludarabine. The patient experienced Grade IV cytokine release syndrome (CRS) and went into complete remission (CR) after anti-inflammatory treatment including tocilizumab. Because of persistent pancytopenia and full donor chimerism, the same donor's conditioning-free peripheral blood stem cells were successfully transplanted 55 days post CAR-T. Neutrophils were engrafted at day +11 and platelets were rebuilt at day +47 without obvious acute graft-versus-host disease (GVHD), but there was mild chronic GVHD in the skin and eyes. Currently, active anti-rejection therapy is still underway. Conclusion: Unedited HLA-matched allogeneic CAR-T cell therapy could be an innovative, effective, and safe treatment for children with refractory/relapse BL without obvious acute GVHD. Conditioning-free allogeneic hematopoietic stem cell transplantation (HSCT) from the same donor is feasible for a patient with full donor T-cell chimerism after allogeneic CAR-T. It cannot be ignored that close GVHD monitoring is needed post HSCT.
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Linfoma de Burkitt , Transplante de Células-Tronco Hematopoéticas , Receptores de Antígenos Quiméricos , Masculino , Humanos , Criança , Adolescente , Receptores de Antígenos Quiméricos/genética , Linfoma de Burkitt/genética , Linfoma de Burkitt/terapia , Linfócitos T , Imunoterapia AdotivaRESUMO
The strategic position of the core area of the Huaihai Economic Zone is very important. The evaluation and analysis of the listed companies' innovation ability in this core area effectively reflect the level of innovation ability of regional enterprises and uncover the differences and influencing factors of the enterprise innovation ability level across different cities and industries; this would provide a reference for further improving the enterprise innovation ability level in the Huaihai Economic Zone. Given this context, data are collected from the CSMAR database on 37 listed companies in eight cities in the Huaihai Economic Zone core area from 2017 to 2021, and an innovation ability evaluation index is constructed from the innovation input and innovation output dimensions of listed companies. The results show that the innovation ability of listed companies in the region is weak; the main reason for the lack of innovation ability of listed companies is the lack of capital investment and talent investment; the innovation primacy of Xuzhou listed enterprises is not high. Finally, in view of the improvement of the innovation ability of listed enterprises in the core field, corresponding suggestions are put forward from the aspects of increasing innovation investment, optimizing the innovation environment and improving the innovation leading force in Xuzhou.
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Indústrias , Investimentos em Saúde , Cidades , Bases de Dados Factuais , Sugestão , ChinaRESUMO
Juvenile myelomonocytic leukaemia (JMML) is an aggressive paediatric leukaemia characterized by mutations in five canonical RAS pathway genes, including the NF1 gene. JMML is driven by germline NF1 gene mutations, with additional somatic aberrations resulting in the NF1 biallelic inactivation, leading to disease progression. Germline mutations in the NF1 gene alone primarily cause benign neurofibromatosis type 1 (NF1) tumours rather than malignant JMML, yet the underlying mechanism remains unclear. Here, we demonstrate that with reduced NF1 gene dose, immune cells are promoted in anti-tumour immune response. Comparing the biological properties of JMML and NF1 patients, we found that not only JMML but also NF1 patients driven by NF1 mutations could increase monocytes generation. But monocytes cannot further malignant development in NF1 patients. Utilizing haematopoietic and macrophage differentiation from iPSCs, we revealed that NF1 mutations or knockout (KO) recapitulated the classical haematopoietic pathological features of JMML with reduced NF1 gene dose. NF1 mutations or KO promoted the proliferation and immune function of NK cells and iMacs derived from iPSCs. Moreover, NF1-mutated iNKs had a high capacity to kill NF1-KO iMacs. NF1-mutated or KO iNKs administration delayed leukaemia progression in a xenograft animal model. Our findings demonstrate that germline NF1 mutations alone cannot directly drive JMML development and suggest a potential cell immunotherapy for JMML patients.
Assuntos
Leucemia Mielomonocítica Juvenil , Neurofibromatose 1 , Animais , Humanos , Leucemia Mielomonocítica Juvenil/genética , Leucemia Mielomonocítica Juvenil/terapia , Leucemia Mielomonocítica Juvenil/metabolismo , Neurofibromina 1/genética , Genes da Neurofibromatose 1 , Mutação em Linhagem Germinativa , Neurofibromatose 1/genética , Neurofibromatose 1/terapia , Mutação , Imunidade , Células Germinativas/metabolismo , Células Germinativas/patologiaRESUMO
OBJECTIVE: To investigate the safety and feasibility of laparoscopic resection of focal nodular hyperplasia (FNH) in the hepatic caudate lobe. METHODS: The clinical data of eight patients who underwent laparoscopic hepatic caudate lobe FNH resection at the Department of Hepatobiliary Surgery, Southwest Hospital, First Affiliated Hospital of Army Medical University, were retrospectively analyzed. RESULTS: The laparoscopic procedures were successful in all eight patients, and no patients required conversion to open surgery. Five patients underwent partial caudate lobe resection, one patient underwent caudate lobe resection, and two patients underwent combined left hemihepatectomy with caudate lobe resection. Tumor resection was performed using the left approach in five cases, the right approach in one case, the middle hepatic fissure approach in one case, and the left and right combined approach in one case. The operation time ranged from 120 to 360 min, with a mean of 225 min. The intraoperative blood loss ranged from 50 to 600 ml, with a mean of 235 ml. No postoperative bleeding, bile leakage or abdominal infection occurred. CONCLUSIONS: Laparoscopic resection of hepatic caudate lobe FNH was safe and feasible in appropriate patients. Skilled laparoscopic hepatectomy techniques, adequate preoperative evaluation, appropriate choice of surgical approach and the control of intraoperative bleeding are critical to perform this surgery.
Assuntos
Hiperplasia Nodular Focal do Fígado , Laparoscopia , Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/cirurgia , Hiperplasia Nodular Focal do Fígado/cirurgia , Estudos Retrospectivos , Resultado do Tratamento , Hepatectomia/métodos , Laparoscopia/métodosRESUMO
Human DDX5 and its yeast ortholog Dbp2 are ATP-dependent RNA helicases that play a key role in normal cell processes, cancer development, and viral infection. The crystal structure of the RecA1-like domain of DDX5 is available but the global structure of DDX5/Dbp2 subfamily proteins remains to be elucidated. Here, we report the first X-ray crystal structures of the Dbp2 helicase core alone and in complex with ADP at 3.22 Å and 3.05 Å resolutions, respectively. The structures of the ADP-bound post-hydrolysis state and apo-state demonstrate the conformational changes that occur when the nucleotides are released. Our results showed that the helicase core of Dbp2 shifted between open and closed conformation in solution but the unwinding activity was hindered when the helicase core was restricted to a single conformation. A small-angle X-ray scattering experiment showed that the disordered amino (N) tail and carboxy (C) tails are flexible in solution. Truncation mutations confirmed that the terminal tails were critical for the nucleic acid binding, ATPase, and unwinding activities, with the C-tail being exclusively responsible for the annealing activity. Furthermore, we labeled the terminal tails to observe the conformational changes between the disordered tails and the helicase core upon binding nucleic acid substrates. Specifically, we found that the nonstructural terminal tails bind to RNA substrates and tether them to the helicase core domain, thereby conferring full helicase activities to the Dbp2 protein. This distinct structural characteristic provides new insight into the mechanism of DEAD-box RNA helicases.