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Accidental oil spills into the ocean can lead to downward transport and settling of oil onto the seafloor as part of marine snow, as seen during the Deepwater Horizon incident in 2010 in the Gulf of Mexico. The arctic and subarctic regions may favor conditions leading to this benthic oil deposition, prompting questions about the potential impacts on benthic communities. This study investigated the effects of oil-contaminated marine snow uptake on the blue mussel (Mytilus sp.). We exposed mussels for four days to 1) oil-contaminated marine snow (MOS treatment), or to 2) chemically-enhanced water-accommodated fraction (CEWAF) of oil plus unaggregated food particles (CEWAF treatment). Both oil treatments received the same nominal concentration of oil and food. Two controls were included: 1) Clean seawater plus unaggregated food (agg-free control) and 2) clean seawater plus marine snow (marine snow control). After the exposure, mussels were allowed to recover for ten days under clean, running seawater. Samples were taken right before and after the exposure period, and after the recovery phase for the following endpoints: distribution (partitioning) of oil compounds between seawater and MOS, and between seawater and mussel tissue; DNA damage (assessed via the comet assay); clearance rate; and condition index [tissue dry weight (g) divided by shell length (mm)]. Some discernable patterns were found in the partitioning of oil compounds between seawater and MOS. However, these patterns did not translate to any significant differences in the partitioning of oil compounds into mussel tissue between the two oil treatments. DNA damage did not exceed background levels (10% tail DNA or less; to be expected in healthy, viable cells) at any sampling time point, but significantly higher DNA damage was observed in CEWAF-T compared to MOS-T mussels after the recovery phase. After the exposure, a significant difference emerged in the clearance rate between the CEWAF treatment and the agg-free control, but not between the MOS treatment and the marine snow control. All mussels except those from the CEWAF treatment exhibited an increased condition index after the exposure time. Together, these results suggest that aggregates could moderate the effects of oil exposure on blue mussels, possibly by providing better, more concentrated nutrition than unaggregated food particles.
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Objective: To construct a repetitive implantation failure (RIF)-related competitive endogenous RNA (ceRNA) regulatory network and validate with clinical samples. Methods: RIF-related long non-coding RNA (lncRNA), microRNA (miRNA) and messenger RNA (mRNA) from the high-throughput gene expression omnibus (GEO) database Expression profile data set were obtained to construct a ceRNA regulatory network of lncRNA-miRNA-mRNA. At the same time, weighted gene co-expression network analysis (WGCNA) was used to explore hub genes in the network. This retrospective study collected RIF patients and controls (at least one pregnancy history after assisted conception) who underwent in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) for assisted pregnancy from 2020 to 2021 at the Reproductive Medicine Center of the First Affiliated Hospital of Zhengzhou University. In the endometrial tissue of patients with 1 pregnancy history, real-time fluorescence quantitative polymerase chain reaction (qRT-PCR) was used to verify the mRNA expression levels of RIF-related hub genes, and Western blotting and immunohistochemistry were used to verify protein expression levels of vascular cell adhesion molecule-1 (VCAM1). Results: A RIF-related ceRNA regulatory network consisting of 32 lncRNAs, 31 miRNAs and 88 mRNAs was constructed, and 7 RIF-related hub genes were identified using WGCNA. By intersecting 88 mRNAs and hub genes in the ceRNA network, two RIF-related key genes were obtained, i.e., VCAM1 and interleukin-2 receptor α (interleukin-2 receptor α, IL-2RA). In clinical verification, the ages of the control group and RIF group [M (Q1, Q3)] were 26.50 (25.00, 34.00) and 30.50 (25.75, 35.25) years old, respectively (P>0.05). Compared with the control group, the mRNA [0.30 (0.15, 0.42) vs 0.99 (0.69, 1.34), P=0.001] and protein expression [0.44 (0.16, 1.27) vs 2.39 (1.58, 2.58), P<0.001] of VCAM1 in the endometrium of the RIF group were both reduced. Conclusions: This study uses bioinformatics analysis methods to construct a RIF-related ceRNA regulatory network, and it is confirmed through clinical samples that the expression level of VCAM1 in the endometrial tissue of RIF patients is significantly reduced.
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Implantação do Embrião , Fertilização in vitro , Redes Reguladoras de Genes , RNA Endógeno Competitivo , Feminino , Humanos , Gravidez , Implantação do Embrião/genética , Endométrio/metabolismo , Perfilação da Expressão Gênica , MicroRNAs/genética , Estudos Retrospectivos , RNA Endógeno Competitivo/genética , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Injeções de Esperma Intracitoplásmicas , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
The study focused on individuals with influenza-like symptoms (fever, cough, sore throat, runny nose, and other respiratory symptoms) in three kindergartens in Tongzhou District, Beijing City, in April 2023. Nasopharyngeal swab specimens were collected, and real-time fluorescent quantitative PCR was used to detect common respiratory pathogens in the collected specimens. Positive specimens were subjected to sequencing analysis of the highly variable region of human respiratory syncytial virus (HRSV) G protein, homology analysis and phylogenetic tree analysis. A total of 25 fever cases were collected from 3 kindergartens, aged 3-8 years old, with an age M (Q1, Q3) of 4 (3.5, 5) years old. Ten confirmed cases of HRSV positive were screened and detected using the fluorescent quantitative PCR method, with a total detection rate of 40% (10/25). Typing identification and sequencing analysis confirmed that the main epidemic type was HRSV subtype B, which was highly homologous and closely related to previous epidemic strains in the region. Through pathogen investigation and analysis, it was preliminarily determined that this epidemic was dominated by HRSV subtype B.
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Filogenia , Infecções por Vírus Respiratório Sincicial , Vírus Sincicial Respiratório Humano , Humanos , Pré-Escolar , Infecções por Vírus Respiratório Sincicial/epidemiologia , Infecções por Vírus Respiratório Sincicial/virologia , Criança , Vírus Sincicial Respiratório Humano/genética , Vírus Sincicial Respiratório Humano/isolamento & purificação , Masculino , Feminino , Pequim/epidemiologia , China/epidemiologiaRESUMO
To analyze the changes in lactate dehydrogenase, creatine kinase, creatine kinase isoenzyme, high-sensitivity troponin T, N-terminal B-type natriuretic peptide precursor, homocysteine, and novel inflammatory indices (neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, systemic immune-inflammation index) before and after competitions in amateur marathon runners, and to assess the effects of myocardial injury due to acute exercise and the value of novel inflammatory indices in marathon exercise monitoring. This paper is an analytical study. Amateur athletes recruited by Beijing Hospital to participate in the 2022 Beijing Marathon and the 2023 Tianjin Marathon, and those who underwent health checkups at the Beijing Hospital Medical Checkup Center from January to June 2023 were selected as the study subjects, and 65 amateur marathon runners (41 males and 24 females) and 130 healthy controls (82 males and 48 females) were enrolled in the study according to the inclusion criteria. Peripheral blood was collected one week before, immediately after, and one week after running, and routine blood tests, cardiac enzymes, infarction markers, N-terminal B-type natriuretic peptide precursor, and homocysteine were performed to calculate the values of novel inflammatory indexes. Wilcoxon signed-rank test and Spearman's rank correlation analysis were used to compare the differences in the levels of each index between the amateur marathon population and the health checkup population, and to compare the changes and correlations of each index at the three time points in the amateur marathoners.The results showed that the neutrophil-lymphocyte ratios of the healthy physical examination population and 65 amateur marathoners 1 week before running were 1.73 (1.33, 2.16) and 1.67 (1.21, 2.16), the platelet-lymphocyte ratios were 122.75 (96.69, 155.89) and 120.86 (100.74, 154.63), and the systemic immune inflammation index was 398.62 (274.50, 538.69) and 338.41 (258.62, 485.38), etc.; on 1 week before running, immediately after running and 1 week after running, lactate dehydrogenase of 65 amateur marathon runners was 173.00(159.00, 196.50)U/L,284.00(237.50, 310.50)U/L, 183.00(165.50, 206.50)U/L, creatine kinase was 131.00(94.30, 188.20)U/L,318.00(212.00, 573.15)U/L,139.00(90.55, 202.40)U/L, creatine kinase isoenzyme was 2.50(1.76, 3.43)µg/L,6.24(4.87, 10.30)µg/L,2.73(1.57, 4.40)µg/L.In 65 amateur marathon runners, lactate dehydrogenase, creatine kinase, creatine kinase isoenzyme, high sensitivity troponin T, N-terminal B-type natriuretic peptide precursor, homocysteine, and novel inflammation markers were significantly elevated in the immediate post-run period compared with 1 week before the run, and the differences were statistically significant (Z=-7.009, Z=-6.813, Z=-6.885, Z=-7.009, Z=-7.009, Z=-6.656; P<0.05 for the above indicators).Neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, and systemic immune-inflammatory index all showed significant positive correlation with the pre-and post-run rates of change of high-sensitivity troponin T (ρ=0.28, P=0.03;ρ=0.31, P=0.01;ρ=0.27, P=0.03); these 3 markers were also significantly and positively correlated with the pre-and post-run rates of change in a collection of myocardial-related markers such as lactate dehydrogenase, creatine kinase, creatine kinase isozymes, high-sensitivity troponin T, N-terminal B-type natriuretic peptide precursor, and homocysteine, respectively(r=0.446, P=0.039; r=0.452, P=0.033; r=0.449, P=0.036).In addition, the platelet-lymphocyte ratio was positively correlated with the pre-and post-run rates of change in creatine kinase and creatine kinase isoenzymes(ρ=0.27, P=0.03;ρ=0.28, P=0.02).In conclusion, acute myocardial injury may be triggered during marathon exercise. Changes in novel inflammatory markers were significantly associated with changes in myocardial enzymes, infarction markers, N-terminal B-type natriuretic peptide precursors, and homocysteine, which may be of value for the prediction of myocardial injury during exercise.
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Creatina Quinase , Inflamação , Corrida de Maratona , Humanos , Masculino , Feminino , Adulto , Creatina Quinase/sangue , L-Lactato Desidrogenase/sangue , Pessoa de Meia-Idade , Estudos de Casos e Controles , Troponina T/sangue , Corrida/fisiologia , Linfócitos , Neutrófilos , Peptídeo Natriurético Encefálico/sangueRESUMO
A space-resolved vacuum ultraviolet spectroscopy is employed to measure impurity emission profiles (500-3200 Å) on EAST. This study successfully captures C IV (1548.20 and 1550.77 Å) lines emitted from carbon ions and derives ion temperatures using Doppler broadening and a collision model based on their intensity ratios. Both the emission intensity and ion temperature profiles are determined. However, the calculated results reveal a lower temperature of around 10-20 eV with the collision model, suggesting a potential need for further correction in subsequent calculations. Furthermore, this study explores relative rotation velocities from the Doppler shift, indicating an increase in toroidal rotation velocity with applied neutral beam injection. The measured results exhibit concordance with the charge exchange recombination spectrometer data. Furthermore, during boron powder dropping discharges on EAST, B II (1623.60, 1623.79, 1623.95, 1624.02, 1624.17, and 1624.38 Å) emission lines exhibiting a similar time behavior trend with boron powder injection are identified. Ion temperatures are measured using B II (1362.46 Å) through the Doppler broadening method. These techniques hold significant promise for future impurity analysis at the edge of EAST, providing valuable insights into the behavior of carbon and boron ions.
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Objective: To analyze the current adoption of palliative care by patients with unresectable metastatic colorectal cancer (mCRC) in China. Methods: From 1 March 2023 to 30 June 2023, a questionnaire survey was conducted by random sampling. An exclusive research platform for the Blue Book on Clinical Diagnosis and Treatment of Metastatic Colorectal Cancer. An online questionnaire was sent to medical oncologists (including chief physicians, associate chief physicians, attending physicians and residents) in general hospitals and oncology hospitals in four major regions of East, Central, South and Northeast China. The questionnaire contained 28 questions requesting basic information about doctors, the number of patients with mCRC, the status of treatment from first to fourth line and beyond, points concerning treatment of pain in patients with mCRC, and expectations for the future. A medical team was responsible for the quality control of data collected, whereas statisticians performed the data cleaning and sorting and statistical analysis. Results: A total of 300 clinical questionnaires were collected, including 217 (72%) from doctors in general hospitals and 83 (28%) from doctors in oncology hospitals. Senior physicians (including associate chief physicians and chief physicians) accounted for 65% of the respondents, attending physicians 30%, and residents 5%. Within 3 months (average for each month), 46.4±26.6% patients were diagnosed with recurrent or unresectable mCRC by each physician, 51.6±26.8% of the patients being in cancer hospitals and 44.4±26.3% in general hospitals. One hundred percent of patients receiving first-line treatment received palliative care, as did 80.3% of those receiving second-line treatment, 58.2% of those receiving third-line treatment, and 35.1% of those receiving ≥fourth-line treatment. The primary factor governing selection of first-line treatment was guideline recommendations, whereas comorbidities and the patients' physical status dictated second line to fourth line treatment. Standard first-line treatment was administered to 93.8% of eligible patients, standard second-line treatment to 94.3%; and standard third-line treatment to 73.5%. First-line therapy included targeted therapy in 63.6% of patients and immunotherapy in 2.8%; second-line therapy included targeted therapy in 63.0% of patients and immunotherapy in 2.0%; third-line therapy included targeted therapy in 59.2% of patients and immunotherapy in 2.2%; and fourth-line therapy included targeted therapy in 48.7% of patients and immunotherapy in 3.1%. First-line treatment lasted an average of 9.6 months, second-line treatment 6.7 months, third-line treatment 4.9 months, and fourth-line treatment 3.7 months. More than 70% of the patients maintained a good quality of life after receiving first and second-line treatment and more than 60% of them had ECOG performance scores of 0-1. After receiving third- and fourth-line treatment, 50%-60% of patients maintained a good quality of life and 40%-50% of them maintained ECOG performance scores of 0-1. The survey also revealed that the main deficiencies in treatment were limited effectiveness of third-line treatment, insufficient availability and opportunity for clinical research, popularity of new drugs or new drug combination strategies, and limited channels for participation in multidisciplinary diagnosis and treatment. Clinicians reported looking forward to participating in more clinical research on new drugs, hearing about the experience of experts in the field, and discovery of new targets and new drugs that increased the options for posterior line treatment of colorectal cancer. Conclusions: This report objectively summarizes the current situation, treatment difficulties, and expectations of frontline physicians concerning management of mCRC, thus providing a basis for decision-making and future direction for the diagnosis and research on treatment of mCRC.
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Neoplasias Colorretais , Cuidados Paliativos , Humanos , Cuidados Paliativos/métodos , Neoplasias Colorretais/terapia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/tratamento farmacológico , Inquéritos e Questionários , China , Metástase Neoplásica , Oncologistas , Feminino , MasculinoRESUMO
BACKGROUND: APG-1387 is a novel second mitochondrial-derived activator of caspases mimetic, small-molecule inhibitor targeting inhibitor of apoptosis proteins. We report results from two phase I trials evaluating the tolerability, safety, and antitumor activity of APG-1387 monotherapy and APG-1387 plus toripalimab [a programmed cell death 1 (PD-1) inhibitor] for advanced solid tumors. PATIENTS AND METHODS: Participants aged ≥18 years who had histologically confirmed advanced solid tumors with no appropriate standard of care (or refractory to standard care) were eligible. Patients received escalating intravenous doses of APG-1387 alone or combined with fixed-dose toripalimab (240 mg every 3 weeks) in a '3 + 3' design. Primary endpoints were dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) in the monotherapy trial, and recommended phase II dose (RP2D) in the combination therapy trial. Secondary endpoints included the pharmacokinetic and pharmacodynamic profiles and preliminary efficacy in both trials. RESULTS: In the monotherapy trial, 28 subjects were enrolled and received ≥1 treatment cycle. No DLT was reported among the 28 subjects, and the MTD was not reached. One participant (3.6%) had a grade ≥3 treatment-related adverse event (TRAE) of alanine aminotransferase elevation. In efficacy analysis of 23 participants, none achieved an objective response, and the disease control rate was 21.7%. In the combination trial, 22 subjects were enrolled and included in all analyses. There was one DLT of grade 3 lipase elevation. The MTD was not reached. Four grade ≥3 TRAEs occurred in three participants (13.6%), with the most common being lipase elevation (n = 2). The RP2D was 45 mg weekly. The objective response rate was 13.6%, with complete response achieved in one subject, and the disease control rate was 54.5%. CONCLUSIONS: APG-1387 45 mg weekly plus toripalimab was well tolerated and is recommended for further study, with preliminary clinical activity observed in study participants with advanced solid tumors.
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Objectives: To investigate clinical characteristics, outcomes and antimicrobial resistance of community-acquired Pseudomonas aeruginosa (CAPA) infections in Chinese pediatric patients. Methods: This retrospective study was conducted at 6 tertiary hospitals in China during January 2016 to December 2018. The clinical and microbiological data of CAPA infected hospitalized children in Hainan and in other regions were collected and compared, and the antimicrobial resistance patterns, clinical characteristics and antibiotic therapy were analyzed. Between different groups were compared using the Chi-square test and Mann-Whitney U test. Results: Among 91 patients, 63 cases were males, 28 cases were females, and 74 cases were from Hainan province, 17 cases were from other regians. The age of consultation was 22.5 (5.4, 44.0) months. Twenty-four cases (26%) had underlying diseases. Fever (79 cases (87%)) and cough (64 cases (70%)) were common initial symptoms. Other concomitant symptoms included wheezing 8 cases (9%), diarrhea 3 cases (3%) and vomiting 4 cases (4%). Twenty-eight cases (31%) had organ infections, including pneumonia 22 cases (24%), skin infection 5 cases (5%), meningitis, intra-abdominal infection and upper urinary tract infection each 1 case (1%). The resistance rate of CAPA isolates to cefepime (4% (4/90)), amikacin (1% (1/90)), ciprofloxacin (2% (2/90)) and levofloxacin (1% (1/89)) was low, and to ceftazidime, piperacillin, piperacillin-azobactam, carbapenem was 12% (11/90), 3/16, 18% (10/56) and 6% (5/90), respectively. Antimicrobial combination therapy accounted for 52% (47/91) of empirical therapy and 59% (52/88) of definite therapy. Two cases (2%) were hopeless discharged, and 3 cases (3%) died during hospitalization. The worse prognosis of CAPA infection is significantly different among children in other regions and in Hainan (4/17 vs. 1% (1/74), χ²=9.74, P<0.05). Conclusions: The invasive CAPA-infection has regional difference in incidence and prognosis in China. Clinical symptoms and signs are non-specific. CAPA strains isolated from pediatric patients display low level of resistance to most of the common antipseudomonal antibiotics. The proportion of poor prognostic outcome is lower in Hainan than in other regions.
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Antibacterianos , Infecções Comunitárias Adquiridas , Infecções por Pseudomonas , Pseudomonas aeruginosa , Humanos , Masculino , Feminino , Infecções Comunitárias Adquiridas/microbiologia , Infecções Comunitárias Adquiridas/tratamento farmacológico , Infecções Comunitárias Adquiridas/epidemiologia , Estudos Retrospectivos , Pseudomonas aeruginosa/isolamento & purificação , Pseudomonas aeruginosa/efeitos dos fármacos , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/epidemiologia , Infecções por Pseudomonas/microbiologia , Antibacterianos/uso terapêutico , Pré-Escolar , Lactente , China/epidemiologia , Testes de Sensibilidade Microbiana , Criança , Farmacorresistência Bacteriana Múltipla , Centros de Atenção TerciáriaRESUMO
Objective: To establish a two-stage surgical procedure of impacted mandibular third molars (IMTMs) extractions assisted by coronectomy and microimplant anchorage traction and to investigate the influencing factors of root movement and the effects of different traction angles on the clinical outcomes. Methods: Fifty-three IMTM in contact with inferior alveolar nerve (IAN) that underwent tooth extraction in the Peking University School of Stomatology from January 2022 to June 2023 were included, with coronectomy and microimplant anchorage implantation in the first stage of the surgery, root traction was achieved with orthodontic elastic and microimplant anchorages by about 600 g of force, when the IMTM root was detached from IAN, a second surgery was performed to extract the residual root. The basic information of patients and M3M, data on the microimplant anchorage implantation and traction, imaging measurements, and complications were recorded and analyzed. Results: The movement distance of the residual roots was (1.80±0.92) mm, and the duration of traction was (32.9±7.9) d. Multiple linear regression analysis showed that the residual root movement distance was significantly correlated with age, gender, number of roots, traction angle, and depth of the distal bone defect of the second molar (P<0.05). The smaller the traction angle, the more significant the movement of the residual roots (P=0.044). In one case (1.9%, 1/53), the patient experienced abnormal sensation in the lower lip 16 days after traction. Conclusions: The two-stage surgical method of combined coronectomy with rapid traction technique to extract the IMTM allows for rapid movement of the residual root and reduces the risk of IAN injury. The efficiency of root movement can be accelerated by appropriately reducing the traction angle during surgery. The traction effect can be predicted based on indicators such as age, gender, number of roots and depth of distal bone defects of second molar.
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In recent years, the application of minimal residual disease (MRD) in solid tumors has gained widespread attention. MRD typically refers to the presence of residual cancer cells that remain undetectable by imaging after curative treatments, such as surgical resection. The presence of MRD post-surgery is significantly associated with an increased risk of tumor recurrence. In colorectal cancer, circulating tumor DNA (ctDNA) serves as an effective marker for assessing MRD, particularly in non-metastatic (stages I-III) colorectal cancer. As a real-time, accurate, and convenient biomarker, ctDNA can effectively predict tumor recurrence, guide postoperative adjuvant chemotherapy decisions, and provide crucial information for recurrence monitoring. The application prospects of ctDNA detection technology are vast, promising more precise and individualized treatment plans for colorectal cancer patients. This article comprehensively analyzes the progress in the application of ctDNA for detecting MRD in non-metastatic colorectal cancer patients, elaborates on its guiding role in clinical treatment decisions, and envisions the future development directions in this field.
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DNA Tumoral Circulante , Neoplasias Colorretais , Neoplasia Residual , Humanos , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/patologia , DNA Tumoral Circulante/sangue , Recidiva Local de Neoplasia , Biomarcadores Tumorais , Quimioterapia AdjuvanteRESUMO
Objective: To assess the capability of seven reference medical laboratories to detect BCR::ABL1 p210 transcription levels and to compare the results among those laboratories. Methods: The interlaboratory comparison was carried out in two stages. The samples were prepared by the reference laboratory. The quantitative values of BCR::ABL1 p210 of the comparison samples covered 0.001%-0.01%, 0.01%-0.1%, 0.1%-1%, 1%-10% and>10% in each stage. Real-time quantitative PCR (RT-PCR) and dPCR (digital PCR) were used to examine the samples. The conversion factor (CF) was calculated and validated for each laboratory. Results: In the RT-PCR comparison, one laboratory was failed to detect BCR::ABL1 p210 in fourteen samples at the first stage. The results of the other six laboratories were qualified with the bias <±1.2 folds (-0.133-0.338) and 95% limits of agreement within ±5 folds (upper limit 0.147-0.785, lower limit -0.770--0.109), and the corresponding CF values were calculated and validated. In the dPCR comparison, one laboratory did not report results at the second stage. The results of the other six laboratories were qualified with the bias <±1.2 folds (-0.026-0.267) and 95% limits of agreement within±5 folds (upper limit 0.084-0.991, lower limit -0.669--0.135), and the corresponding CF values were calculated and validated. The samples with BCR::ABL1 p210 quantitative values of 0.01%-0.1%, 0.1%-1%, 1%-10% and >10% could be detected by both RT-PCR and qPCR. When the quantitative value of BCR::ABL1 p210 was 0.001%-0.01%, the detection rate of dPCR was higher than that of RT-PCR (85.56% vs. 68.00%). Conclusions: A good consistency is present among various laboratories. The quantitative value of BCR::ABL1 p210 is comparable among laboratories as shown by the CF value conversion. For quantitative detection of BCR::ABL1 p210 deep molecular reaction, dPCR has a higher positive detection rate and more advantages than RT-PCR. To ensure the accuracy and reproducibility of the BCR::ABL1 p210 test, it is imperative for every laboratory to enhance their daily quality control practices.
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Proteínas de Fusão bcr-abl , Reação em Cadeia da Polimerase em Tempo Real , Humanos , Proteínas de Fusão bcr-abl/genética , Reação em Cadeia da Polimerase em Tempo Real/métodos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Reprodutibilidade dos TestesRESUMO
We retrospectively analyzed the clinical data of seven patients (four men and three women) with primary hyperoxaluria (PH) type 1 (PH1) in the Department of Nephrology of Zhongda Hospital, Southeast University from January 2018 to October 2023. The mean age at disease onset was 32.1 (range: 26-42) years. The mean age at diagnosis was 40.6 (range: 28-51) years. All patients initially had kidney stones, and three patients were found to have renal insufficiency at the time of disease onset. Among them, two patients underwent hemodialysis immediately. Symptoms at the first visit included bone pain (n=7), joint pain or deformity (n=5), fatigue (n=5), hypotension (n=3), and subcutaneous nodules (n=2). Four patients had a family history of PH. All patients had varying degrees of anemia (60-114 g/L), significant hypoalbuminemia (16.5-32.1 g/L), and hypercoagulable state (D-dimer: 2 230-12 781 µg/L). Seven patients received maintenance hemodialysis; their mean age was 37.7 (range: 26-50) years. The mean duration from disease onset to hemodialysis was 5.6 (range: 0-20) years. Five patients repeatedly experienced dialysis access dysfunction. Three patients underwent kidney transplantation before a diagnosis was made, and all transplanted kidneys lost function due to oxalate deposition. The mean follow-up duration was 14.43 (range: 4-38) months. Unfortunately, one patient died. All seven patients underwent computed tomography of the abdomen. All patients suffered skeletal abnormalities, bilateral nephrolithiasis, and nephrocalcinosis. Six patients carried AGXT gene mutations, including four compound heterozygous mutations and two pure homozygous mutations.The mutation sites included: c.823-824dup.AG (p.S275Rfs*38)(exon 8), c.815-816ins.GA (p.S275Rfs*38)(exon 8), c.595G>A (p.G199S) (exon 5), c.32C>G (p.P11R) (exon 1), and c.638C>T (p.A213V)(exon 6). According to the American College of Medical Genetics and Genomics guidelines, two loci were identified as likely pathogenic variants, seven were identified as pathogenic variants, and one locus was identified as having uncertain significance. In addition, patients 1 and 4 underwent skin biopsy, patient 2 underwent renal transplant biopsy, and patient 3 underwent bone marrow biopsy. Interestingly, significant oxalate deposition was found in the tissues. Therefore, PH1 is a rare autosomal recessive inherited disease. This study not only enhanced the understanding of the clinical characteristics of PH1 patients but also had great significance in early diagnosis and treatment of the disease.
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Hiperoxalúria Primária , Mutação , Diálise Renal , Humanos , Masculino , Hiperoxalúria Primária/diagnóstico , Hiperoxalúria Primária/genética , Hiperoxalúria Primária/complicações , Feminino , Adulto , Estudos Retrospectivos , Pessoa de Meia-Idade , Cálculos Renais/diagnóstico , Transplante de RimRESUMO
OBJECTIVE: To investigate the mechanism of 2, 6-dimethoxy-1, 4-benzoquinone (DMQ), an active ingredients in fermented wheat germ extract, for inhibiting NLRP3 inflammasome activation and alleviating septic shock in mice. METHODS: Cultured murine bone marrow-derived macrophages (BMDM) stimulated with lipopolysaccharide (LPS) were treated with DMQ, followed by treatment with Nigericin, ATP, and MSU for activating the canonical NLRP3 inflammasome; the noncanonical NLRP3 inflammasome was activated by intracellular transfection of LPS, and AIM2 inflammasome was activated using Poly A: T.In human monocytic THP-1 cells, the effect of Nigericin on inflammasome activation products was examined using Western blotting and ELISA.Co-immunoprecipitation was performed to explore the mechanism of DMQ-induced blocking of NLRP3 inflammasome activation.In a male C57BL/6J mouse model of LPS-induced septic shock treated with 20 and 40 mg/kg DMQ, the levels of IL-1ß and TNF-α in the serum and peritoneal lavage fluid were determined using ELISA, and the survival time of the mice within 36 h was observed. RESULTS: Treatment with DMQ effectively inhibited LPS-induced activation of canonical NLRP3 inflammasome in mouse BMDM and human THP-1 cells and also inhibited non-canonical NLRP3 inflammasome activation in mouse BMDM, but produced no significant effect on AIM2 inflammasome activation.DMQ significantly blocked the binding between ASC and NLRP3.In the mouse models of septic shock, DMQ treatment significantly reduced the levels of IL-1ß in the serum and peritoneal fluid and obviously prolonged survival time of the mice. CONCLUSION: DMQ can effectively block ASC-NLRP3 interaction to inhibit NLRP3 inflammasome activation and alleviate LPSinduced septic shock in mice.
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Benzoquinonas , Inflamassomos , Interleucina-1beta , Lipopolissacarídeos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR , Choque Séptico , Animais , Choque Séptico/tratamento farmacológico , Choque Séptico/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Camundongos , Inflamassomos/metabolismo , Masculino , Humanos , Benzoquinonas/farmacologia , Benzoquinonas/uso terapêutico , Interleucina-1beta/metabolismo , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Células THP-1 , Modelos Animais de DoençasRESUMO
OBJECTIVE: To investigate the cell membrane-penetrating capacity of human cell-penetrating peptide hPP10 carrying human antioxidant protein Cu-Zn superoxide dismutase (Cu, Zn-SOD) and assess the antioxidant and anti-inflammatory activity of these fusion proteins. METHODS: The fusion protein hPP10-Cu, Zn-SOD was obtained by genetic engineering and identified by Western blotting. The membrane-penetrating ability of the fusion protein was evaluated by immunofluorescence assay, fluorescence colocalization assay and Western blotting, its SOD enzyme activity was detected using a commercial kit, and its effect on cell viability was assessed with MTT assay. In a HEK293 cell model of H2O2-induced oxidative stress, the effect of hPP10-Cu, Zn-SOD on cell apoptosis was analyzed with flow cytometry and RT-qPCR, and its antioxidant effect was assessed using reactive oxygen species (ROS) assay; its anti-inflammatory effect was evaluated in mouse model of TPA-induced ear inflammation by detecting expression of the inflammatory factors using RT-qPCR, Western blotting and immunohistochemistry. RESULTS: The fusion protein hPP10-Cu, Zn-SOD was successfully obtained. Immunofluorescence assay confirmed obvious membrane penetration of this fusion protein in HEK293 cells, localized both in the cell membrane and the cell nuclei after cell entry. hPP10-Cu, Zn-SOD at the concentration of 5 µmol/L exhibited strong antioxidant activity with minimal impact on cell viability at the concentration up to 10 µmol/L. The fusion protein obviously inhibited apoptosis and decreased intracellular ROS level in the oxidative stress cell model and significantly reduced mRNA and protein expression of the inflammatory factors in the mouse model of ear inflammation. CONCLUSION: The fusion protein hPP10-Cu, Zn-SOD capable of penetrating the cell membrane possesses strong antioxidant and anti-inflammatory activities with only minimal cytotoxicity, demonstrating the value of hPP10 as an efficient drug delivery vector and the potential of hPP10-Cu, Zn-SOD in the development of skincare products.
Assuntos
Anti-Inflamatórios , Antioxidantes , Apoptose , Peptídeos Penetradores de Células , Estresse Oxidativo , Superóxido Dismutase , Humanos , Camundongos , Antioxidantes/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Células HEK293 , Estresse Oxidativo/efeitos dos fármacos , Peptídeos Penetradores de Células/farmacologia , Apoptose/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Membrana Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Proteínas Recombinantes de Fusão/farmacologia , Inflamação/metabolismo , Peróxido de HidrogênioRESUMO
BACKGROUND: High tumor mutational burden (TMB) is one of the widely researched predictive biomarkers of immune checkpoint inhibitors and has been shown to be closely related with response to immunotherapy in multiple cancer types. However, for patients who have failed conventional therapy and are about to undergo immunotherapy, there is no consensus recommendation on the timing of tumor sampling for TMB analysis, and the effects of different therapies on TMB have not been clarified. This retrospective observational study aimed to investigate the heterogeneity of TMB and genomic mutation under the treatment pressure. PATIENTS AND METHODS: We retrospectively collected the available genomic and therapeutic information from 8051 samples across 15 tumor types (>50 samples/tumor) found in 30 published studies and investigated the distribution and heterogeneity of TMB under treatment across diverse cohorts. RESULTS: This integrated analysis has shown anticancer treatments increased TMB. Significant effects of treatment on TMB were more frequently observed in tumor types with lower treatment-naïve TMB, including breast, prostate, and pediatric cancers. For different cancer therapies, chemotherapy was prone to be correlated with an increased TMB in most cancer types. Meanwhile, the fraction of the TMB-high category of breast, prostate, and bladder cancers and glioma increased significantly after chemotherapy. Several actionable genes including ERS1 and NF1 in breast cancer, as well as some prognostic markers including TERT in bladder cancer and IDH1 in glioma, were significantly changed in post-chemotherapy tumors compared to treatment-naïve tumors. CONCLUSION: Our study reveals the heterogeneity of TMB under treatment across diverse cancer types and provides evidences that chemotherapy was associated with increases in TMB as well as the fraction of TMB-high category, suggesting that resampling tumor tissues for calculating post-chemotherapy TMB could be a better option for predicting the response to immunotherapy, especially for tumors with initially low TMB.
Assuntos
Biomarcadores Tumorais , Mutação , Neoplasias , Feminino , Humanos , Biomarcadores Tumorais/genética , Genômica/métodos , Imunoterapia/métodos , Neoplasias/genética , Neoplasias/tratamento farmacológico , Estudos RetrospectivosRESUMO
BACKGROUND AND AIM: Preeclampsia, a pregnancy complication associated with significant maternal and perinatal mortality and morbidity, has been found to be closely linked to dysfunction in the blood coagulation-fibrinolysis system. However, the relationship between hematologic data and severity and onset time of preeclampsia remains unclear. This study aimed to identify specific hematologic parameters in both preeclamptic and normotensive pregnant women and determine their potential significance in the pathogenesis of preeclampsia. MATERIALS AND METHODS: A total of 112 patients with gestational hypertension disease were divided into two groups: early-onset preeclampsia (32 cases) and late-onset preeclampsia (80 cases). A control group of 82 normotensive pregnant women matched for age and parity was also selected. Blood samples were collected from all participants to test for specific hematologic parameters. RESULTS: Mild and severe preeclampsia were associated with lower hemoglobin level (P = 0.01 and P = 0.03, respectively), higher mean platelet volume (P = 0.01 and P = 0.01, respectively) and fibrinogen (P = 0.01 and P = 0.01, respectively), and shorter prothrombin time (P = 0.02 and P = 0.01, respectively) and activated partial thromboplastin time (P = 0.01 and P = 0.02, respectively). CONCLUSION: These findings have provided evidence on the hematologic coagulative actors in the pathogenesis and severity of preeclampsia.
Assuntos
Pré-Eclâmpsia , Humanos , Feminino , Gravidez , Adulto , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/fisiopatologia , Pré-Eclâmpsia/diagnóstico , Estudos de Casos e Controles , Hipertensão Induzida pela Gravidez/sangue , Hipertensão Induzida pela Gravidez/fisiopatologia , Coagulação Sanguínea/fisiologia , Índice de Gravidade de Doença , Adulto Jovem , Fibrinogênio/metabolismo , Fibrinogênio/análise , Tempo de Protrombina , Volume Plaquetário Médio , Hemoglobinas/análise , Tempo de Tromboplastina ParcialRESUMO
Located at the interface of the dentin-pulp complex, the odontoblasts are specialized cells responsible for dentin synthesis and nociceptive signal detection in response to external stimuli. Recent studies have shown that the mechanosensitive ion channel PIEZO1 is involved in bone formation and remodeling through the influx of calcium ions, and it is abundantly expressed in odontoblasts. However, the specific role of PIEZO1 in reactionary dentinogenesis and the underlying mechanisms remain elusive. In this study, we found intense PIEZO1 expression in the plasma membrane and cytoplasm of odontoblasts in healthy human third molars, mouse mandibular molars, and human odontoblast-like cells (hOBLCs). In hOBLCs, PIEZO1 positively regulated DSPP, DMP1, and COL1A1 expression through the Ca2+/PI3K-Akt/SEMA3A signaling pathway. In addition, exogenous SEMA3A supplementation effectively reversed reduced mineralization capacity in PIEZO1-knockdown hOBLCs. In vivo, Piezo1 expression peaked at day 7 and returned to baseline at day 21 in a wild-type mice dentin injury model, with Sema3a presenting a similar expression pattern. To investigate the specific role of PIEZO1 in odontoblast-mediated reactionary dentinogenesis, mice with a conditional knockout of Piezo1 in odontoblasts were generated, and no significant differences in teeth phenotypes were observed between the control and conditional knockout (cKO) mice. Nevertheless, cKO mice exhibited reduced reactionary dentin formation and decreased Sema3a and Dsp positive staining after dentin injury, indicating impaired dental pulp repair by odontoblasts. In summary, these findings suggest that PIEZO1 enhances the mineralization capacity of hOBLCs in vitro via the Ca2+/PI3K-Akt/SEMA3A signaling pathway and contributes to reactionary dentinogenesis in vivo.