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In recent years, immune checkpoint inhibitors (ICIs) have been widely used in malignant solid tumors with remarkable efficacy. However, in colorectal cancer (CRC), ICIs have shown significant therapeutic effects only in patients with highly microsatellite unstable/mismatch repair-deficient metastatic CRC and these patients are only a minority of all CRC patients. In contrast, the majority of patients, those with microsatellite stable (MSS)/mismatch repair-complete (pMMR)-type metastatic CRC, could hardly benefit from ICI monotherapies, and immune combination therapies have become the key to solveing this clinical challenge. This article introduces the common patterns and possible mechanisms of immune-combination therapies for MSS/pMMR-type CRC, the exploration and progress made in the application of immune-combination therapies, as well as the possible predictive markers of efficacy of immune therapies. The prospects and directions of ICIs in the treatment of MSS/pMMR-type CRC are also discussed.
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Neoplasias Colorretais , Inibidores de Checkpoint Imunológico , Instabilidade de Microssatélites , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/administração & dosagem , Imunoterapia/métodos , Reparo de Erro de Pareamento de DNARESUMO
Objective: To investigate the association between cytokines and ocular chronic graft-versus-host disease (cGVHD) and identify specific biomarkers for ocular cGVHD to enhance clinical diagnosis, treatment, and evaluation. Methods: A mouse model of cGVHD was established to explore the correlation between cGVHD and serum cytokines. Based on the findings from the animal experiments and literature review, a panel of 16 cytokine combinations was identified. Enzyme-linked immunosorbent assay (ELISA) was used to compare the cytokine concentrations in the serum and tear samples from patients who underwent allogeneic hematopoietic stem cell transplantation from June 2017 to March 2022 at the Medical Center of Hematology, Xinqiao Hospital, Army Medical University. Results: â Compared with the control group, mice with cGVHD exhibited elevated serum IL-1ß, IL-6, IL-8, IL-17, IFN-γ, CX3CL1, CXCL11, CXCL13, CCL11, and CCL19 concentrations (all P<0.05). â¡ Analysis of the cytokine profiles of the serum and tear samples revealed that compared with patients without ocular cGVHD, those with ocular cGVHD exhibited increased serum IL-8 [P=0.032, area under the curve (AUC) =0.678]; decreased serum IL-10 (P=0.030, AUC=0.701) ; elevated IL-8, IFN-γ, CXCL9, and CCL17 in tear samples; and lower IL-10 and CCL19 in tear samples (all P<0.05, all AUC>0.7). Moreover, cytokines in tear samples showed correlations with ocular surface parameters related to ocular cGVHD. Conclusions: Tear fluid demonstrates greater specificity and sensitivity as a biomarker for diagnosing ocular cGVHD than serum biomarkers. Among the identified cytokines in tear samples, IL-8, IL-10, IFN-γ, CXCL9, CCL17, and CCL19 serve as diagnostic biomarkers for ocular cGVHD post-transplantation, offering practical reference value for diagnosis.
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Citocinas , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Lágrimas , Animais , Humanos , Camundongos , Biomarcadores/metabolismo , Doença Crônica , Citocinas/metabolismo , Citocinas/sangue , Modelos Animais de Doenças , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/metabolismo , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Interferon gama/sangue , Interferon gama/metabolismo , Lágrimas/metabolismo , Transplante HomólogoRESUMO
To find a way to control the electron-bunching process and the bunch-emitting directions when an ultraintense, linearly polarized laser pulse interacts with a nanoscale target, we explored the mechanisms for the periodical generation of relativistic attosecond electron bunches. By comparing the simulation results of three different target geometries, the results show that for nanofoil target, limiting the transverse target size to a small value and increasing the longitudinal size to a certain extent is an effective way to improve the total electron quantity in a single bunch. Then the subfemtosecond electronic dynamics when an ultrashort ultraintense laser grazing propagates along a nanofoil target was analyzed through particle-in-cell simulations and semiclassical analyses, which shows the detailed dynamics of the electron acceleration, radiation, and bunching process in the laser field. The analyses also show that the charge separation field produced by the ions plays a key role in the generation of electron bunches, which can be used to control the quantity of the corresponding attosecond radiation bunches by adjusting the length of the nanofoil target.
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OBJECTIVES: The purpose of our study was to assess the multiscalar changes in leprosy burden and its associated risk factors over the last three decades. STUDY DESIGN: We conducted an in-depth examination of leprosy's spatial-temporal trends at multiple geographical scale (global, regional, and national), utilizing information from Global Burden of Disease, Injuries, and Risk Factors Study (GBD 2019). METHODS: Incidence and the estimated annual percentage change (EAPC) in age-standardized incidence rate (ASIR) of leprosy were determined, with countries categorized based on leprosy incidence changes. We examined socioeconomic and physical geography influences on leprosy incidence via Spearman correlation analysis, using ternary phase diagrams to reveal the synergetic effects on leprosy occurrence. RESULTS: Globally, incident cases of leprosy decreased by 27.86% from 1990 to 2019, with a reduction in ASIR (EAPC = -2.53), yet trends were not homogeneous across regions. ASIR and EAPC correlated positively with sociodemographic index (SDI), and an ASIR growth appeared in high SDI region (EAPC = 3.07). Leprosy burden was chiefly distributed in Tropical Latin America, Oceania, Central Sub-Saharan Africa, and South Asia. Negative correlations were detected between the incidence of leprosy and factors of SDI, GDP per capita, urban population to total population, and precipitation, whereas the number of refugee population, temperature, and elevation showed opposite positive results. CONCLUSIONS: Despite a global decline in leprosy over the past three decades, the disparities of disease occurrence at regional and national scales still persisted. Socioeconomic and physical geographic factors posed an obvious influence on the transmission risk of leprosy. The persistence and regional fluctuations of leprosy incidence necessitate the ongoing dynamic and multilayered control strategies worldwide in combating this ancient disease.
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Carga Global da Doença , Hanseníase , Humanos , Geografia , Hanseníase/epidemiologia , Exame Físico , Fatores Socioeconômicos , Saúde Global , Incidência , Anos de Vida Ajustados por Qualidade de VidaRESUMO
OBJECTIVE: The present study aimed to compare the effect of topical laryngeal lidocaine with intravenous lidocaine before endotracheal intubation on the incidence and severity of postoperative sore throat, hoarseness, and cough. PATIENTS AND METHODS: This prospective randomized controlled study enrolled 144 patients undergoing laparoscopic cholecystectomy with endotracheal intubation. The patients were randomized to three groups and received 2% lidocaine by topical laryngeal spray (group T), intravenous 2% lidocaine (group I), and the equivalent volume of intravenous saline (group C) before intubation. The incidence and severity of sore throat, hoarseness, and cough reaction at 0.5, 1, 6, and 24 h after extubation were collected. RESULTS: The incidence of sore throat was significantly lower in group T than in groups I and C (6.4% vs. 37.2% and 86.7%, p < 0.001), respectively at 0.5 h after extubation, and it was significantly lower in group I than that in group C (37.2% vs. 86.7%, p < 0.001). Both the incidence of hoarseness and cough were significantly lower in group T than in group I and in group C (14.9% vs. 97.7% and 97.8%, p < 0.001, and 19.1% vs. 72.0% and 93.3%, p < 0.001), respectively. The severity of sore throat, hoarseness and cough in group T was significantly lower than that in group I and that in group C (p < 0.05), and it was significantly lower in group I than in group C (p < 0.05). CONCLUSIONS: Both topical laryngeal lidocaine and intravenous lidocaine before intubation have positive effects on preventing sore throat. Topical laryngeal route was superior to intravenous route. Chictr.org.cn ID: ChiCTR2100042442.
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Anestésicos Locais , Faringite , Humanos , Extubação/efeitos adversos , Anestésicos Locais/uso terapêutico , Tosse/etiologia , Tosse/complicações , Rouquidão/epidemiologia , Rouquidão/etiologia , Rouquidão/prevenção & controle , Intubação Intratraqueal/efeitos adversos , Lidocaína/uso terapêutico , Faringite/epidemiologia , Faringite/etiologia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/prevenção & controle , Estudos ProspectivosRESUMO
OBJECTIVE: To assess the efficacy of pirfenidone combined with PD-L1 inhibitor for treatment of bladder cancer in a mouse model and its effect on tumor immune microenvironment modulation. METHODS: Forty C57BL/6 mouse models bearing ectopic human bladder cancer xenografts were randomized into control group, PD-L1 inhibitor group, pirfenidone group and combined treatment group (n=10). After successful modeling, PD-L1 inhibitor treatment was administered via intraperitoneal injection at 12.5 mg/kg every 3 days, and oral pirfenidone (500 mg/kg) was given on a daily basis. The survival rate of the mice and tumor growth rate were compared among the 4 groups. The expressions of CD3, CD8, CD45, E-cadherin and N-cadherin in the tumor tissues were detected with immunohistochemistry after the 21-day treatment, and bone marrow-derived suppressor cells (MDSCs) were observed with immunofluorescence staining; serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea nitrogen (BUN), creatinine (CRE) and lactate dehydrogenase (LDH-L) were analyzed using an automated biochemical analyzer. RESULTS: Treatment with PD-L1 inhibitor and pirfenidone alone both significantly decreased tumor growth rate and tumor volume at 21 days (P < 0.05), but the combined treatment produced an obviously stronger inhibitory effect (P < 0.05). PD-L1 inhibitor and pirfenidone alone significantly increased E- cadherin expression and decreased N-cadherin expression in the tumor tissue (P < 0.05). The two treatments both significantly increased the percentage of CD3+, CD8 and CD45+ T cells and decreased the percentage of Ly-6G+CD11b+MDSCs in the tumor tissue, and these changes were more obvious in the combined treatment group (P < 0.05). No significant differences were found in serum ALT, AST, BUN, CRE or LDH-L levels among the 4 groups (P>0.05). CONCLUSION: Combined treatment with pirfenidone and PD-L1 inhibitor significantly inhibits the progression of bladder cancer in mice possibly by regulating tumor immune microenvironment and inhibiting epithelial-mesenchymal transition of the tumor cells.
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Inibidores de Checkpoint Imunológico , Piridonas , Neoplasias da Bexiga Urinária , Humanos , Camundongos , Animais , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Xenoenxertos , Antígeno B7-H1/metabolismo , Camundongos Endogâmicos C57BL , Linfócitos T CD8-Positivos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , Caderinas , Microambiente TumoralRESUMO
1. Laying performance is an important economic trait in poultry. The blood is essential in transporting nutrients to the yolk and albumen and is necessary for egg formation.2. This study calculated the phenotypic relationships of duck egg quality, egg production efficiency and 22 serum parameters in the egg-laying stage. Using a variety of methodologies, a genome-wide association study (GWAS) was carried out to uncover the genetic foundations of the 22 serum biochemical markers of laying ducks.3. Spearman correlation coefficients between the egg production (226-329 per day) and the serum parameters were all weak, being less than 0.3. This analysis was done on 22 serum parameters, with total protein (TP), total triglycerides (TG), calcium (Ca) and phosphorous (P) having the highest correlation coefficients (r = 0.56-0.88). The coefficients for blood markers, such as total cholesterol (CHOL), total bilirubin (TBIL), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) varied from 0.70-0.94.4. Based on single-marker single-trait genome-wide analyses by a mixed linear model program of EMMAX, nine candidate genes were associated with enzyme traits (AST/ALT aspartate transaminase/glutamic-pyruvic transaminase, creatine kinase) and 19 candidate genes were associated with metabolism and protein-related serum parameters (glucose, total bile acid, uric acid (UA), albumin (ALB).5. The mvLMM (multivariate linear mixed model) of GEMMA software was used to carry out multiple trait integrated GWAS. Two candidate genes were found in the TP-TG-CA-P analysis and seven candidate genes in the CHOL_LDL-C_HDL-C_TBIL study. There was a high genetic correlation between the two groups.
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Patos , Estudo de Associação Genômica Ampla , Animais , Patos/genética , Estudo de Associação Genômica Ampla/veterinária , LDL-Colesterol , Galinhas , Albuminas , Aspartato Aminotransferases , HDL-ColesterolRESUMO
Objective: To investigate the distribution and hantavirus (HV) carrying state in host animals of hemorrhagic fever with renal syndrome (HFRS) in Henan Province from 2019 to 2022. Methods: Host animal monitoring was carried out at the monitoring sites of HFRS in Henan Province. The real-time fluorescence quantitative PCR was used to detect hantavirus in rat lungs. The types of hantavirus were analyzed. The positive samples were sequenced and then sequence homology and variation were analyzed. Results: A total of 1 308 rodents were captured from 2019 to 2022, 16 specimens of rat lungs tested positive for hantavirus nucleic acid. The positive rate of HV was 1.22% (16/1 308). According to type, the positive rate of HV in Apodius agrarius was the highest (68.75%, 11/16). According to distribution, the positive rate of HV in field samples was the highest (2.50%, 12/480), and the positive rate of HV in residential samples was 0.53% (4/759). The typing results of 16 positive samples showed that all viruses were hantavirus type â (hantaan virus). The positive samples were sequenced and eight S gene fragments (GenBank number: OQ681444-OQ681451) and six M gene fragments (OQ681438-OQ681443) were obtained. The S and M gene fragments were similar to the Shaanxi 84FLi strain and Sichuan SN7 strain. Phylogenetic analysis of S and M gene fragments showed that they all belonged to the hantaan virus-H5 subtype. Amino acid sequence analysis revealed that, compared with the hantaan virus vaccine strain 84FLi, the 74th amino acid encoded by eight S fragments was replaced by aspartamide with serine. Tryptophan was replaced by glycine at the 14th position of Gn region in XC2022047, and isoleucine was replaced by alanine at the 359 position of XC2022022 and XC2022024. Conclusion: The hantavirus carried by host animals in Henan Province from 2019 to 2022 belongs to the type â (hantaan virus), and Apodemus agrarius is still the dominant host animal of the hantaan virus. Compared with the vaccine strains, amino acid sites are replaced in the immune epitopes of the S and M gene fragments.
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Febre Hemorrágica com Síndrome Renal , Orthohantavírus , Vacinas , Animais , Febre Hemorrágica com Síndrome Renal/epidemiologia , Filogenia , Orthohantavírus/genética , Murinae , Aminoácidos/genéticaRESUMO
Circular RNAs are implicated in the pathogenesis of ischemic stroke. In this work, we explored the modulation and potential mechanisms of action of circ_0005585 in ischemic stroke. Expression of circ_0005585 and miR-16-5p was assessed by quantitative real-time reverse transcription PCR. Ischemic stroke was modeled in mice by middle cerebral artery occlusion (MCAO). The infarct volume was assessed by triphenyl tetrazolium chloride staining. Neurological deficits were evaluated according to Neurological Severity Score. The permeability of the blood-brain barrier was assessed by Evan's blue leakage and brain water content. Apoptosis in brain tissues was measured by the TUNEL test. Relative expression of apoptosis-related proteins was evaluated by Western blotting. The direct interaction between circ_0005585 and miR-16-5p was verified by dual-luciferase reporter assay. The expression of circ_0005585 was lower in mice with MCAO. Lentivirus-mediated overexpression of circ_0005585 ameliorated the neurological deficits and decreased the infarction volume in MCAO mice. The brain water content and Evan's blue leakage through the blood-brain barrier were reduced. In addition, overexpression of circ_0005585 inhibited apoptosis in the cerebral tissues. Our results revealed direct interaction between circ_0005585 and miR-16-5p. Hence, circ_0005585 protects mouse brain during ischemic stroke by targeting miR-16-5p, which uncovers the pathogenesis of this pathology and opens new vitas for its therapy.
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Isquemia Encefálica , AVC Isquêmico , MicroRNAs , Traumatismo por Reperfusão , Camundongos , Animais , Isquemia Encefálica/metabolismo , Azul Evans , MicroRNAs/genética , MicroRNAs/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , Apoptose/genética , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/metabolismoRESUMO
1. A study was conducted to evaluate the effects of dietary cholecalciferol (vitamin D3) and 25-hydroxycholecalciferol (25-OH-D3) supplementation on the reproductive performance, egg quality, eggshell ultrastructure, serum hormone level and antioxidant capacity, intestinal morphology and tibia quality of breeder geese during the laying period.2. The trial was designed as a 3 × 3 factorial arrangement with three levels (300, 400 and 500 IU/kg) of vitamin D3 supplementation and three levels (25, 50 and 75 µg/kg) of 25-OH-D3 supplementation in a 10-wk feeding trial.3. The results showed that the combined supplementation of 400 IU/kg vitamin D3 and 50 µg/kg 25-OH-D3 had a better feed conversion ratio and a higher egg laying rate than the other groups. Vitamin D3 supplementation significantly increased the rate of qualified eggs for hatching, eggshell strength and thickness, serum testosterone and progesterone levels, serum total superoxide dismutase and glutathione peroxidase activities, tibia ash content and bone mineral density (P < 0.05). Dietary 25-OH-D3 supplementation significantly increased serum glutathione peroxidase activity and duodenal villus height and villus height-to-crypt-depth ratio (P < 0.05). The geese receiving 500 IU/kg vitamin D3 and 75 µg/kg 25-OH-D3 had the highest tibia calcium and phosphorous content among all groups (P < 0.05).4. Feeding 400 IU/kg vitamin D3 plus 50 µg/kg 25-OH-D3 gave optimal effects on feed conversion ratio and egg laying rate. This combination could be a nutritional strategy for increasing the laying rate, eggshell quality, serum hormone levels and serum antioxidant function regardless of 25-OH-D3 supplementation. Supplementation of 50 µg/kg 25-OH-D3 could be a recommended dose for improving the serum antioxidant capacity and intestinal morphology regardless of vitamin D3 supplementation.
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Calcifediol , Colecalciferol , Animais , Ração Animal/análise , Antioxidantes , Galinhas , Colecalciferol/farmacologia , Dieta/veterinária , Suplementos Nutricionais , Gansos , Glutationa Peroxidase , Hormônios , Óvulo , TíbiaRESUMO
BACKGROUND: Little is known about the multi-dimensional nature of traumatic duty-related events encountered by firefighters in relation to their post-traumatic stress disorder (PTSD) risk. AIMS: To describe the types of duty-related events encountered by career firefighters and explore if years in the fire service or total event load moderated the association of trauma exposure to PTSD symptoms. METHODS: Participants included 755 career, male firefighters (19% of the department's firefighters and 76% of those who accessed the electronic anonymous survey). The Duty-Related Incident Stressors scale was used to assess exposure to 25 potentially traumatic events (event load) and self-appraisal of the stress associated with these events, grouped by type of event (indirect, direct and colleague-related). The Post-Traumatic Stress Disorder Checklist was used to assess PTSD symptoms. RESULTS: Firefighters rated colleague-related events as the most stressful, followed by indirect and direct events. Event load (râ =â 0.25) and indirect, direct and colleague-related events stress (râ =â 0.32-0.35) were positively associated with PTSD symptoms. Results of moderation analyses indicated that event load served as a risk factor in the relation of indirect events stress to PTSD symptoms, and as a buffer in the relation of direct events stress to PTSD symptoms. Years in the fire service were not associated with PTSD symptoms nor moderated the relation of event stress to PTSD symptoms. CONCLUSIONS: Findings underscored the importance of considering the differential effects that types of duty-related traumatic events and cumulative exposure to trauma may have on firefighters' PTSD symptoms.
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AIM: To assess the value of semi-quantitative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and quantitative diffusion-weighted imaging parameters combined with human epididymis protein 4 (HE4) in predicting the pathological grade and lymphovascular space invasion (LVSI) of endometrioid adenocarcinoma (EAC). MATERIALS AND METHODS: Between October 2018 and December 2021, 60 women (mean age, 55 [range, 32-77] years) with EAC underwent preoperative pelvic MRI and HE4 level measurements. The positive enhancement integral (PEI), time to peak, maximum slope of increase (MSI), and maximum slope of decrease were measured by manually drawing a region of interest on the neoplastic tissue. The receiver operating characteristic curve was used to calculate the diagnostic efficiency of the single parameter and combined factors. RESULTS: Lower apparent diffusion coefficients (ADCs) were observed in high-grade tumours (G3) than in low-grade tumours (G1/G2). PEI, MSI, and HE4 levels were higher in the high-grade tumours than in the low-grade tumours (p<0.05). The area under the curve (AUC) for G3 diagnosis using multiparametric MRI combined with HE4 was 0.929. ADC values were significantly lower in the EAC with LVSI than in those without LVSI. Tumours with LVSI showed higher PEI and HE4 levels than those without LVSI (p<0.05). The AUC for LVSI-positive diagnosis using multiparametric MRI combined with HE4 was 0.814. CONCLUSION: Semi-quantitative DCE-MRI, ADC values, and serum HE4 levels can be used to predict tumour grade and LVSI, and the prediction efficiency of multiparametric MRI combined with serum HE4 is better than that of any single factor.
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Carcinoma Endometrioide , Imageamento por Ressonância Magnética Multiparamétrica , Feminino , Humanos , Pessoa de Meia-Idade , Biomarcadores Tumorais , Carcinoma Endometrioide/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética/métodos , Imageamento por Ressonância Magnética/métodos , Estudos Retrospectivos , Adulto , IdosoRESUMO
Measurement bias (MB) has been described in causal structures but is still not entirely clear. In practice, the correctness of substitution estimate (SE) of effect is a prerequisite for causal inference, usually based on a bidirectionally non-differential misclassification between the measured exposure and the measured outcome. Based on a directed acyclic graph (DAG), this paper proposes a structure for the single-variable measure, where its MB is derived from the choice of an imperfect, "input/output device-like" measurement system. The MB of the SE is influenced both by the measurement system itself and by factors outside the measurement system: while the independence or dependence mechanism of the measurement system still ensures that the MB of the SE is bidirectionally non-differential; however, the misclassification can be bidirectionally non-differential, unidirectionally differential, or bidirectionally differential resulted from the factors outside the measurement system. In addition, reverse causality should be defined at the level of measurement, where measured exposures can influence measured outcomes and vice versa. Combined with temporal relationships, DAGs help elucidate MB's structures, mechanisms, and directionality.
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Fatores de Confusão Epidemiológicos , Humanos , Interpretação Estatística de Dados , Viés , CausalidadeRESUMO
Objective: To preliminarily evaluate the safety and efficacy of shunt-related interventional therapy accompanied with spontaneous portosystemic shunts (SPSS) in patients with hepatic encephalopathy (HE). Methods: Case data on six patients who underwent interventional therapy accompanied by SPSS for HE from January 2017 to March 2021 were collected to evaluate the efficacy and postoperative complications. Results: All six patients underwent SPSS. Four patients had hepatitis B cirrhosis; one had alcoholic cirrhosis; and one had hepatic arterioportal fistula-induced portal hypertension. Child-Pugh liver function scores were C and B in three and three cases, respectively. The SPSS type was gastrorenal shunt in two cases; portal-thoracic-azygos venous in two cases; portal-umbilical-iliac venous in one case; and portal-splenic venous - inferior vena cava in one case. Two of them had previously had a transjugular intrahepatic portosystemic shunt (TIPS), and there were SPSS prior to TIPS. Five cases (5/6) successfully underwent shunt embolization, and one case (1/6) underwent stent implantation for flow restriction (portal-umbilical-iliac vein). The technical success rate was 100%. HE did not recur during hospitalization or the three-month follow-up period. However, one case had a recurrence of HE within a year after surgery and was treated symptomatically, while another experienced gastrointestinal bleeding a year after surgery.. Conclusion: SPSS embolization or flow restriction is effective and safe for improving HE patients' symptoms.
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Procedimentos Endovasculares , Varizes Esofágicas e Gástricas , Encefalopatia Hepática , Hipertensão Portal , Derivação Portossistêmica Transjugular Intra-Hepática , Humanos , Derivação Portossistêmica Transjugular Intra-Hepática/efeitos adversos , Encefalopatia Hepática/complicações , Hipertensão Portal/etiologia , Varizes Esofágicas e Gástricas/etiologia , Cirrose Hepática/complicações , Procedimentos Endovasculares/efeitos adversos , Resultado do Tratamento , Hemorragia Gastrointestinal/etiologiaRESUMO
Objective: To investigate the genetic and genomic profiling of juvenile myelomonocytic leukemia (JMML) and factors affecting its survival rate. Methods: Clinical characteristics, cytogenetics, molecular biology results and survival status of children with 27 JMML cases admitted to the Hematology Department of Children's Hospital, Capital Institute of Pediatrics from December 2012 to December 2021 were analyzed retrospectively, and the outcomes of the children were followed up. Kaplan-Meier method was used for survival analysis. Univariate analysis was used for analyzing factors affecting the overall survival (OS) rates of patients who received hematopoietic stem cell transplantation (HSCT). Log-Rank test was used for comparison of survival curves. Results: Among 27 JMML cases, there were 11 males and 16 females. The age of disease onset was 28 (11,52) months. There are 20 cases of normal karyotype, 4 cases of monosomy 7, 1 case of trisomy 8,1 case of 11q23 rearrangement and 1 case of complex karyotype. A total of 39 somatic mutations were detected.Those involved in RAS signal pathway were the highest (64%(25/39)), among which PTPN11 mutation was the most frequent (44% (11/25)). A total of 17 cases (63%) received HSCT, 8 cases (30%) did not receive HSCT, and 2 cases (7%) lost follow-up. For children receiving transplantation, the follow-up time after transplantation was 47 (11,57) months. The 1-year OS rate of high-risk transplantation group (17 cases) and high-risk non transplantation group (6 cases) was (88±8)% and (50±20)% respectively, with a statistically significant difference (χ2=5.01, P=0.025). The 5-year OS rate of the high-risk transplantation group was (75±11)%. The survival time of those who relapsed or progressed to acute myeloid leukemia after transplantation was significantly shorter than that of those who did not relapse (χ2=6.80, P=0.009). The OS rate of patients with or without PTPN11 mutation was (81±12) % and (67±19)% respectively (χ2=0.85, P=0.356). Conclusions: The main pathogenesis involved in JMML is gene mutation related to RAS signaling pathway, and the most common driver gene of mutation is PTPN11. Allogeneic HSCT can significantly improve the survival rate of high-risk JMML patients. The recurrence or progression after transplantation was related to poor prognosis.
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Transplante de Células-Tronco Hematopoéticas , Leucemia Mielomonocítica Juvenil , Masculino , Feminino , Criança , Humanos , Pré-Escolar , Leucemia Mielomonocítica Juvenil/genética , Leucemia Mielomonocítica Juvenil/terapia , Estudos Retrospectivos , Análise de Sobrevida , MutaçãoRESUMO
BACKGROUND: Genetic predisposition to coronavirus disease 2019 (COVID-19) may contribute to its morbidity and mortality. Because cytokines play an important role in multiple phases of infection, we examined whether commonly occurring, functional polymorphisms in macrophage migration inhibitory factor (MIF) are associated with COVID-19 infection or disease severity. AIM: To determine associations of common functional polymorphisms in MIF with symptomatic COVID-19 or its severity. METHODS: This retrospective case-control study utilized 1171 patients with COVID-19 from three tertiary medical centers in the USA, Hungary and Spain, together with a group of 637 pre-pandemic, healthy control subjects. Functional MIF promoter alleles (-794 CATT5-8,rs5844572), serum MIF and soluble MIF receptor levels, and available clinical characteristics were measured and correlated with COVID-19 diagnosis and hospitalization. Experimental mice genetically engineered to express human high- or low-expression MIF alleles were studied for response to coronavirus infection. RESULTS: In patients with COVID-19, there was a lower frequency of the high-expression MIF CATT7 allele when compared to healthy controls [11% vs. 19%, odds ratio (OR) 0.54 [0.41-0.72], P < 0.0001]. Among inpatients with COVID-19 (n = 805), there was a higher frequency of the MIF CATT7 allele compared to outpatients (n = 187) (12% vs. 5%, OR 2.87 [1.42-5.78], P = 0.002). Inpatients presented with higher serum MIF levels when compared to outpatients or uninfected healthy controls (87 ng/ml vs. 35 ng/ml vs. 29 ng/ml, P < 0.001, respectively). Among inpatients, circulating MIF concentrations correlated with admission ferritin (r = 0.19, P = 0.01) and maximum CRP (r = 0.16, P = 0.03) levels. Mice with a human high-expression MIF allele showed more severe disease than those with a low-expression MIF allele. CONCLUSIONS: In this multinational retrospective study of 1171 subjects with COVID-19, the commonly occurring -794 CATT7MIF allele is associated with reduced susceptibility to symptomatic SARS-CoV-2 infection but increased disease progression as assessed by hospitalization. These findings affirm the importance of the high-expression CATT7MIF allele, which occurs in 19% of the population, in different stages of COVID-19 infection.
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COVID-19 , Fatores Inibidores da Migração de Macrófagos , Humanos , Animais , Camundongos , Estudos Retrospectivos , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Fatores Inibidores da Migração de Macrófagos/genética , Teste para COVID-19 , COVID-19/diagnóstico , COVID-19/genética , SARS-CoV-2 , Predisposição Genética para Doença , Oxirredutases Intramoleculares/genéticaRESUMO
The retraction has been discussed after the authors asked to retract this article due to incorrect attribution and affillation of the authors.
Assuntos
Artrite Experimental , Camundongos , Animais , Hidrogênio , Camundongos Endogâmicos DBA , Interleucinas , Interleucina 22RESUMO
Objective: To trace and characterize the whole genome of SARS-CoV-2 of confirmed cases in the outbreak of COVID-19 on July 31, 2021 in Henan Province. Method: Genome-wide sequencing and comparative analysis were performed on positive nucleic acid samples of SARS-CoV-2 from 167 local cases related to the epidemic on July 31, 2021, to analyze the consistency and evolution of the whole genome sequence of virus. Results: Through high-throughput sequencing, a total of 106 cases of SARS-CoV-2 whole genome sequences were obtained. The results of genome analysis showed that the whole genome sequences of 106 cases belonged to the VOC/Delta variant strain (B.1.617.2 clade), and the whole genome sequences of 106 cases were shared with the genomes of 3 imported cases from Myanmar admitted to a hospital in Zhengzhou. On the basis of 45 nucleotide sites, 1-5 nucleotide variation sites were added, and the genome sequence was highly homologous. Conclusion: Combined with the comprehensive analysis of viral genomics, transmission path simulation experiments and epidemiology, it is determined that the local new epidemic in Henan Province is caused by imported cases in the nosocomial area, and the spillover has caused localized infection in the community. At the same time, it spills over to some provincial cities and results in localized clustered epidemics.