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1.
Neurochem Int ; : 105791, 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38880231

RESUMO

Long-term studies have confirmed a causal relationship between the development of neurodegenerative processes and vitamin B1 (thiamine) deficiency. However, the biochemical mechanisms underlying the high neurotropic activity of thiamine are not fully understood. At the same time, there is increasing evidence that vitamin B1, in addition to its coenzyme functions, may have non-coenzyme activities that are particularly important for neurons. To elucidate which effects of vitamin B1 in neurons are due to its coenzyme function and which are due to its non-coenzyme activity, we conducted a comparative study of the effects of thiamine and its derivative, 3-decyloxycarbonylmethyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazolium chloride (DMHT), on selected processes in synaptosomes. The ability of DMHT to effectively compete with thiamine for binding to thiamine-binding sites on the plasma membrane of synaptosomes and to participate as a substrate in the thiamine pyrophosphokinase reaction was demonstrated. In experiments with rat brain synaptosomes, unidirectional effects of DMHT and thiamine on the activity of the pyruvate dehydrogenase complex (PDC) and on the incorporation of radiolabeled [2-14C]pyruvate into acetylcholine were demonstrated. The observed effects of thiamine and DMHT on the modulation of acetylcholine synthesis can be explained by suggesting that both compounds, which interact in cells with enzymes of thiamine metabolism, are phosphorylated and exert an inhibitory/activating effect (concentration-dependent) on PDC activity by affecting the regulatory enzymes of the complex. Such effects were not observed in the presence of structural analogs of thiamine and DMHT without a 2-hydroxyethyl substituent at position 5 of the thiazolium cycle. The effect of DMHT on the plasma membrane Ca-ATPase was similar to that of thiamine. At the same time, DMHT showed high cytostatic activity against neuroblastoma cells.

2.
Zhonghua Yi Xue Za Zhi ; 104(23): 2160-2166, 2024 Jun 18.
Artigo em Chinês | MEDLINE | ID: mdl-38871474

RESUMO

Objective: To investigate the clinical and genetic mutation characteristics of patients with primary hemophagocytic lymphohistiocytosis (HLH) and their impact on prognosis. Methods: Sixty-three primary HLH patients with complete medical records admitted and diagnosed at Beijing Friendship Hospital of Capital Medical University from January 2013 to December 2022 were selected. The patients' clinical and laboratory features, genetic and rapid immunological indicator characteristics, treatment outcomes and prognosis were retrospectively analyzed. Follow-up was up to June 30, 2023, with a median follow-up time [M (Q1, Q3)] of 47 (21, 76) months. Overall survival was analyzed using Kaplan-Meier survival curve, and prognostic factors were analyzed using Cox proportional hazards regression model. Results: Sixty-three primary HLH patients included 35 males and 28 females, with a median age [M (Q1, Q3)] of 17 (7, 27) years. Clinical manifestations at the initial diagnosis mainly included fever (93.7%, 59/63), splenomegaly (87.3%, 55/63), hemophagocytosis (65.1%, 41/63), hepatomegaly (52.4%, 33/63) and central nervous system (CNS) involvement (38.1%, 24/63). A total of 39 patients (61.9%) were diagnosed with EB virus (EBV) infection at initial diagnosis.PRF1 and UNC13D gene mutations were the most common mutations, and the highest frequency mutation site in the PRF1 gene was c.1349C>T, and that of UNC13D gene was c.2588G>A. A total of 76.2% (48/63) of patients had reduced activity of natural killer (NK) cells. Cytotoxic cell degranulation function was impaired or absent in 52.7% (29/55) of patients, of which 79.2% (19/24) of patients with primary HLH with defects in degranulation-related genes had impaired degranulation function. The 1-year and 3-year overall survival rates were 74.8% and 66.7%, respectively. Cox multivariate analysis suggested that peripheral blood EBV≥10 000 copies/ml (HR=3.523, 95%CI: 1.418-8.757, P=0.007) was the risk factor for prognosis. Conclusions: The main clinical manifestations of primary HLH patients at the initial diagnosis include fever, splenomegaly, hemophagocytosis, hepatomegaly, and CNS involvement. PRF1 and UNC13D are the most commonly mutated genes. High copy number EBV infection in peripheral blood is the risk factor for prognosis.


Assuntos
Linfo-Histiocitose Hemofagocítica , Mutação , Humanos , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/diagnóstico , Masculino , Prognóstico , Feminino , Estudos Retrospectivos , Adolescente , Criança , Adulto , Adulto Jovem , Perforina/genética
6.
Zhonghua Liu Xing Bing Xue Za Zhi ; 45(3): 325-330, 2024 Mar 10.
Artigo em Chinês | MEDLINE | ID: mdl-38514307

RESUMO

Objective: To explore the prospective associations between physical activity and incident ischemic stroke in adults. Methods: Data of China Kadoorie Biobank study in Tongxiang of Zhejiang were used. After excluding participants with cancers, strokes, heart diseases and diabetes at baseline study, a total of 53 916 participants aged 30-79 years were included in the final analysis. The participants were divided into 5 groups according to the quintiles of their physical activity level. Cox proportional hazard regression models was used to calculate the hazard ratios (HR) for the analysis on the association between baseline physical activity level and risk for ischemic stroke. Results: The total physical activity level in the participants was (30.63±15.25) metabolic equivalent (MET)-h/d, and it was higher in men [(31.04±15.48) MET-h/d] than that in women [(30.33±15.07) MET-h/d] (P<0.001). In 595 526 person-years of the follow-up (average 11.4 years), a total of 1 138 men and 1 082 women were newly diagnosed with ischemic stroke. Compared to participants with the lowest physical activity level (<16.17 MET-h/d), after adjusting for socio-demographic factors, lifestyle, BMI, waist circumference, and SBP, the HRs for the risk for ischemic stroke in those with moderate low physical activity level (16.17-24.94 MET-h/d), moderate physical activity level (24.95-35.63 MET-h/d), moderate high physical activity level (35.64-43.86 MET-h/d) and the highest physical activity level (≥43.87 MET-h/d) were 0.93 (95%CI: 0.83-1.04), 0.87 (95%CI: 0.76-0.98), 0.82 (95%CI: 0.71-0.95) and 0.76 (95%CI: 0.64-0.89), respectively. Conclusion: Improving physical activity level has an effect on reducing the risk for ischemic stroke.


Assuntos
Diabetes Mellitus , AVC Isquêmico , Acidente Vascular Cerebral , Adulto , Masculino , Humanos , Feminino , Estudos Prospectivos , Acidente Vascular Cerebral/epidemiologia , Exercício Físico , China/epidemiologia , Fatores de Risco
7.
Bull Exp Biol Med ; 176(3): 399-402, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38342809

RESUMO

A morphological analysis of the liver of Wistar rats was performed 2 months after a single intravenous injection of porous silicon particles of different sizes (60-80, 250-300, and 500-600 nm; 2 mg/ml, 1 ml). Histological, immunohistochemical, and electron microscopic methods showed the development of CD68+ granulomas in all experimental groups. Injection of 60-80-nm porous silicon particles led to the formation of single large granulomas (>2000 µm2), while 500-600-nm nanoparticles caused the formation of numerous smaller granulomas. The mechanism of involution of granulomas by apoptosis of Kupffer cells and the absence of subsequent connective tissue remodeling of the organ tissue is shown.


Assuntos
Fígado , Silício , Ratos , Animais , Ratos Wistar , Fígado/patologia , Granuloma/induzido quimicamente , Granuloma/patologia , Células de Kupffer
8.
Zh Vopr Neirokhir Im N N Burdenko ; 88(1): 109-114, 2024.
Artigo em Russo | MEDLINE | ID: mdl-38334738

RESUMO

The main problem in microsurgical resection of spinal cord tumors is excessive surgical aggression. The last one often leads to unsatisfactory clinical and neurological outcomes. Laser fluorescence spectroscopy is a modern neurosurgical approach to distinguish tumor boundaries even if standard visible fluorescence techniques are ineffective. OBJECTIVE: To evaluate the effectiveness of laser fluorescence spectroscopy alone or in combination with visual 5-ALA fluorescence for improvement of safety and quality of resection, as well as intraoperative diagnosis. MATERIAL AND METHODS: Searching for literature data was carried out in accordance with the PRISMA recommendations. The authors reviewed articles independently of each other. These data were systematized. RESULTS: Laser fluorescence spectroscopy is valuable to identify fragments of intramedullary ependyomas in 86% of cases, while visual fluorescence only in 81% of cases. Advisability of this technique for low-grade astrocytomas is still unclear and requires further study. Its effectiveness is 87.5% for extramedullary meningiomas. Neuromas do not accumulate 5-ALA. In addition, this method can be used to determine the boundaries of intradural metastatic lesions. CONCLUSION: 5-ALA fluorescence is a safe and useful intraoperative method for identifying tumor tissue and resection margins in patients with intramedullary or infiltrative extramedullary spinal cord tumors. Visual fluorescence combined with laser spectroscopy is a perspective method for intraoperative visualization of tumor remnants. This approach can improve safety and postoperative outcomes while maintaining resection quality.


Assuntos
Neoplasias da Medula Espinal , Neoplasias da Coluna Vertebral , Humanos , Neoplasias da Coluna Vertebral/cirurgia , Espectrometria de Fluorescência , Neoplasias da Medula Espinal/diagnóstico por imagem , Neoplasias da Medula Espinal/cirurgia , Procedimentos Neurocirúrgicos/métodos , Lasers
10.
Int Immunopharmacol ; 128: 111489, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38266450

RESUMO

PURPOSE: To develop a CT-based model to classify pneumonitis etiology in patients with non-small cell lung cancer(NSCLC) after radiotherapy(RT) and Immune checkpoint inhibitors(ICIs). METHODS: We retrospectively identified 130 NSCLC patients who developed pneumonitis after receipt of ICIs only (n = 50), thoracic RT only (n = 50) (ICIs only + thoracic RT only, the training cohort, n = 100), and RT + ICIs (the test cohort, n = 30). Clinical and CT radiomics features were described and compared between different groups. We constructed a random forest (RF) classifier and a linear discriminant analysis (LDA) classifier by CT radiomics to discern pneumonitis etiology. RESULTS: The patients in RT + ICIs group have more high grade (grade 3-4) pneumonitis compared to patients in ICIs only or RT only group (p < 0.05). Pneumonitis after the combined therapy was not a simple superposition mode of RT-related pneumonitis(RP) and ICI-related pneumonitis(CIP), resulting in the distinct characteristics of both RT and ICIs-related pneumonitis. The RF classifier showed favorable discrimination between RP and CIP with an area under the receiver operating curve (AUC) of 0.859 (95 %CI: 0.788-0.929) in the training cohort and 0.851 (95 % CI: 0.700-1) in the test cohort. The LDA classifier achieved an AUC of 0.881 (95 %CI: 0.815-0.947) in the training cohort and 0.842 (95 %CI: 0.686-0.997) in the test cohort. Our analysis revealed four principal CT-based features shared across both models:original_glrlm_LongRunLowGrayLevelEmphasis, wavelet-HLL_firstorder_Median, wavelet-LLL_ngtdm_Busyness, and wavelet-LLL_glcm_JointAverage. CONCLUSION: CT radiomics-based classifiers could provide a noninvasive method to identify the predominant etiology in NSCLC patients who developed pneumonitis after RT alone, ICIs alone or RT + ICIs.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Pneumonia , Pneumonite por Radiação , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Pneumonite por Radiação/complicações , Pneumonite por Radiação/tratamento farmacológico , Estudos Retrospectivos , Radiômica , Tomografia Computadorizada por Raios X/efeitos adversos , Tomografia Computadorizada por Raios X/métodos , Pneumonia/tratamento farmacológico
11.
Ann Surg ; 279(3): 536-541, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-37487006

RESUMO

OBJECTIVE: To determine the impact of nodal basin ultrasound (US) surveillance versus completion lymph node dissection (CLND) in children and adolescents with sentinel lymph node (SLN) positive melanoma. BACKGROUND: Treatment for children and adolescents with melanoma are extrapolated from adult trials. However, there is increasing evidence that important clinical and biological differences exist between pediatric and adult melanoma. METHODS: Patients ≤18 years diagnosed with cutaneous melanoma between 2010 and 2020 from 14 pediatric hospitals were included. Data extracted included demographics, histopathology, nodal basin strategies, surveillance intervals, and survival information. RESULTS: Of 252 patients, 90.1% (n=227) underwent SLN biopsy (SLNB), 50.9% (n=115) had at least 1 positive node. A total of 67 patients underwent CLND with 97.0% (n=65/67) performed after a positive SLNB. In contrast, 46 total patients underwent US observation of nodal basins with 78.3% (n=36/46) of these occurring after positive SLNB. Younger patients were more likely to undergo US surveillance (median age 8.5 y) than CLND (median age 11.3 y; P =0.0103). Overall, 8.9% (n=21/235) experienced disease recurrence: 6 primary, 6 nodal, and 9 distant. There was no difference in recurrence (11.1% vs 18.8%; P =0.28) or death from disease (2.2% vs 9.7%; P =0.36) for those who underwent US versus CLND, respectively. CONCLUSIONS: Children and adolescents with cutaneous melanoma frequently have nodal metastases identified by SLN. Recurrence was more common among patients with thicker primary lesions and positive SLN. No significant differences in oncologic outcomes were observed with US surveillance and CLND following the identification of a positive SLN.


Assuntos
Melanoma , Linfonodo Sentinela , Neoplasias Cutâneas , Adulto , Humanos , Adolescente , Criança , Melanoma/diagnóstico por imagem , Melanoma/cirurgia , Melanoma/patologia , Neoplasias Cutâneas/diagnóstico por imagem , Neoplasias Cutâneas/cirurgia , Linfonodo Sentinela/patologia , Recidiva Local de Neoplasia/patologia , Excisão de Linfonodo , Biópsia de Linfonodo Sentinela , Estudos Retrospectivos
12.
Mol Biol (Mosk) ; 57(6): 1188-1198, 2023.
Artigo em Russo | MEDLINE | ID: mdl-38062968

RESUMO

Metabolic stress caused by a lack of glucose significantly affects the state of red blood cells, where glycolysis is the main pathway for the production of ATP. Hypoglycemia can be both physiological (occurring during fasting and heavy physical exertion) and pathological (accompanying a number of diseases, such as diabetes mellitus). In this study, we have characterized the state of isolated erythrocytes under metabolic stress caused by the absence of glucose. It was established that 24 h of incubation of the erythrocytes in a glucose-free medium to simulate blood plasma led to a two-fold decrease in the ATP level into them. The cell size, as well as intracellular sodium concentration increased. These findings could be the result of a disruption in ion transporter functioning because of a decrease in the ATP level. The calcium level remained unchanged. With a lack of glucose in the medium of isolated erythrocytes, there was no increase in ROS and a significant change in the level of nitric oxide, while the level of the main low-molecular weight thiol of cells, glutathione (GSH) decreased by almost 2 times. It was found that the metabolic stress of isolated red blood cells induced hemoglobin glutathionylation despite the absence of ROS growth. The cause was the lack of ATP, which led to a decrease in the level of GSH because of the inhibition of its synthesis and, probably, due to a decrease in the NADPH level required for glutathione (GSSG) reduction and protein deglutathionylation. Thus, erythrocyte metabolic stress induced hemoglobin glutathionylation, which is not associated with an increase in ROS. This may have an important physiological significance, since glutathionylation of hemoglobin changes its affinity for oxygen.


Assuntos
Glutationa , Hemoglobinas , Dissulfeto de Glutationa/análise , Dissulfeto de Glutationa/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Oxirredução , Glutationa/análise , Glutationa/metabolismo , Hemoglobinas/análise , Hemoglobinas/metabolismo , Eritrócitos/química , Eritrócitos/metabolismo , Estresse Oxidativo , Glucose/análise , Glucose/metabolismo , Trifosfato de Adenosina
13.
Vestn Oftalmol ; 139(5): 60-67, 2023.
Artigo em Russo | MEDLINE | ID: mdl-37942598

RESUMO

The article presents two clinical cases of adenocarcinoma of nonpigmented epithelium of the ciliary body, which is a very rare malignant tumor of the organ of vision with distinctive features. Surgical treatment is necessary to verify this tumor and assess the degree of its aggressiveness in terms of the prognosis of the disease, with subsequent pathomorphological and immunohistochemical studies. The article also discusses the epidemiological aspects, morphological features, clinical manifestations of this pathological condition, as well as possible treatment options and features of follow-up monitoring of this group of patients.


Assuntos
Adenocarcinoma , Neoplasias Uveais , Humanos , Corpo Ciliar/patologia , Corpo Ciliar/cirurgia , Epitélio Pigmentado Ocular/patologia , Neoplasias Uveais/diagnóstico , Neoplasias Uveais/patologia , Epitélio/patologia , Adenocarcinoma/diagnóstico , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia
14.
Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi ; 41(10): 837-840, 2023 Oct 20.
Artigo em Chinês | MEDLINE | ID: mdl-37935550

RESUMO

Objective: To investigate the levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and interleukin-1beta (IL-1ß) in the plasma and bronchoalveolar lavage fluid of silicosis patients with artificial quartz stone plate processing. Methods: In January 2022, 10 patients with artificial quartz stone plate processing silicosis and 20 patients with common silicosis who were hospitalized and diagnosed in a hospital at Zhejiang Province from June 2019 to December 2021 were retrospectively selected as the research objects, and 30 healthy people were selected as the control group during the same period. Plasma of all subjects and bronchoalveolar lavage fluid of all patients were collected. The levels of TNF-α, IL-6 and IL-1ß in plasma and bronchoalveolar lavage fluid were detected by enzyme-linked immunosorbent assay and were analyzed. Results: The levels of TNF-α, IL-6 and IL-1ß in the plasma of patients with silicosis were higher than those of the control group (P<0.05), and the levels of TNF-α and IL-1ß in the plasma of silicosis patients with artificial quartz stone plate processing were higher than those of common silicosis patients (P<0.05). The levels of TNF-α and IL-1ß in plasma of artificial quartz stone plate processing silicosis patients were higher than those of common silicosis patients at the same silicon stage (P<0.05). The levels of IL-1ß in bronchoalveolar lavage fluid of silicosis patients with artificial quartz stone plate processing was higher than that of patients with common silicosis (P<0.05) . Conclusion: The levels of TNF-α, IL-6 and IL-1ß in silicosis patients with artificial quartz stone plate processing are higher than those in patients with common silicosis, which may be related to dust components they are exposed to.


Assuntos
Quartzo , Silicose , Humanos , Interleucina-6 , Fator de Necrose Tumoral alfa , Estudos Retrospectivos , Líquido da Lavagem Broncoalveolar
15.
Artigo em Inglês, Russo | MEDLINE | ID: mdl-37830465

RESUMO

One of the important problems in microsurgical resection of intramedullary spinal cord tumors is excessive surgical aggression and subsequent neurological impairment. Laser fluorescence spectroscopy with electrophysiological monitoring provides high-quality resection of intramedullary tumors with monitoring of spinal cord structures in real time. This approach increases safety and quality of resection. OBJECTIVE: To analyze efficacy of fluorescence navigation technique and laser fluorescence spectroscopy in surgical treatment of various spinal cord tumors. MATERIAL AND METHODS: There were more than 1000 patients with intramedullary spinal cord tumors between 2001 and 2022. Intraoperative fluorescence navigation with laser spectroscopy was used in 47 cases. All patients underwent examination before and after surgery. We analyzed somatic, neurological and functional status (McCormick scale). MRI of the spinal cord and intraoperative fluorescence spectroscopy (OPMI Pentero 900 microscope with a fluorescent module, Carl Zeiss, Germany) were performed. To induce visible fluorescence, we used 5-ALA-Alasens (NIOPIK, Russia). Laser spectroscopy was carried out on a LESA-01-BIOSPEC analyzer (Biospec JSC, Russia). Morphological analysis of intramedullary spinal cord tumors was carried out in the laboratory of neuromorphology of the Burdenko Neurosurgery Center. RESULTS: In our sample, fluorescence navigation and laser fluorescence spectroscopy were used only in surgical treatment of intramedullary tumors. Laser fluorescence spectroscopy was valuable to identify fragments of intramedullary ependymoma and astrocytoma in 86% of cases, visual fluorescence - only in 81% of cases. Advisability of this technique for low-grade astrocytomas is unclear and requires further study. CONCLUSION: Visual fluorescence combined with laser spectroscopy is a promising method for intraoperative imaging of tumor remnants. This approach can improve safety, quality and results of surgical treatment.


Assuntos
Astrocitoma , Ependimoma , Neurocirurgia , Neoplasias da Medula Espinal , Humanos , Espectrometria de Fluorescência , Neoplasias da Medula Espinal/diagnóstico por imagem , Neoplasias da Medula Espinal/cirurgia , Neoplasias da Medula Espinal/patologia , Procedimentos Neurocirúrgicos/métodos , Ependimoma/cirurgia , Lasers , Resultado do Tratamento , Estudos Retrospectivos
16.
Zhonghua Xue Ye Xue Za Zhi ; 44(7): 572-577, 2023 Jul 14.
Artigo em Chinês | MEDLINE | ID: mdl-37749038

RESUMO

Objective: This study aimed to investigate the clinical characteristics of patients diagnosed with primary hemophagocytic lymphohistiocytosis (pHLH) associated with perforin gene deficiency. Methods: We retrospectively analyzed the clinical data of 16 pHLH patients associated with perforin gene deficiency at Beijing Friendship Hospital, Capital Medical University, from April 2014 to August 2021. The mutation sites, mutation types, family history, clinical characteristics, and prognosis of the patients were assessed. Results: A total of 16 patients, including ten males and six females, with a median onset age of 17.5 years (range: 4-42 years), were enrolled in this study. Sixteen different mutations were identified, consisting of 11 missense mutations, one nonsense mutation, two frameshift mutations, and two in-frame mutations. All patients harbored at least one deleterious missense mutation, with the most common mutation sites being c.1349C>T (p.T450M) and c.503G>A (p.S168N). Decreased natural killer (NK) cell activity was observed in 11 patients, reduced perforin protein expression in ten patients, concurrent Epstein-Barr virus (EBV) infection at onset in eight patients, a family history in two patients, and central nervous system involvement in four patients. Eleven cases underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT), with eight cases surviving. The median survival time of non-transplanted patients was eight months (range: 4-18 months), while that of transplanted patients was reported as "not reached". Conclusions: Emphasizing the diagnosis of pHLH in adults with perforin gene deficiency. In addition, it should be noted that EBV infection can potentially act as a triggering factor in such disease, and allo-HSCT exerts a substantial effect on the prognosis of patients.


Assuntos
Infecções por Vírus Epstein-Barr , Linfo-Histiocitose Hemofagocítica , Adulto , Feminino , Masculino , Humanos , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/genética , Herpesvirus Humano 4 , Linfo-Histiocitose Hemofagocítica/genética , Perforina/genética , Estudos Retrospectivos
18.
Ann Oncol ; 34(9): 813-825, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37330052

RESUMO

BACKGROUND: The isolation of cell-free DNA (cfDNA) from the bloodstream can be used to detect and analyze somatic alterations in circulating tumor DNA (ctDNA), and multiple cfDNA-targeted sequencing panels are now commercially available for Food and Drug Administration (FDA)-approved biomarker indications to guide treatment. More recently, cfDNA fragmentation patterns have emerged as a tool to infer epigenomic and transcriptomic information. However, most of these analyses used whole-genome sequencing, which is insufficient to identify FDA-approved biomarker indications in a cost-effective manner. PATIENTS AND METHODS: We used machine learning models of fragmentation patterns at the first coding exon in standard targeted cancer gene cfDNA sequencing panels to distinguish between cancer and non-cancer patients, as well as the specific tumor type and subtype. We assessed this approach in two independent cohorts: a published cohort from GRAIL (breast, lung, and prostate cancers, non-cancer, n = 198) and an institutional cohort from the University of Wisconsin (UW; breast, lung, prostate, bladder cancers, n = 320). Each cohort was split 70%/30% into training and validation sets. RESULTS: In the UW cohort, training cross-validated accuracy was 82.1%, and accuracy in the independent validation cohort was 86.6% despite a median ctDNA fraction of only 0.06. In the GRAIL cohort, to assess how this approach performs in very low ctDNA fractions, training and independent validation were split based on ctDNA fraction. Training cross-validated accuracy was 80.6%, and accuracy in the independent validation cohort was 76.3%. In the validation cohort where the ctDNA fractions were all <0.05 and as low as 0.0003, the cancer versus non-cancer area under the curve was 0.99. CONCLUSIONS: To our knowledge, this is the first study to demonstrate that sequencing from targeted cfDNA panels can be utilized to analyze fragmentation patterns to classify cancer types, dramatically expanding the potential capabilities of existing clinically used panels at minimal additional cost.


Assuntos
Ácidos Nucleicos Livres , DNA Tumoral Circulante , Neoplasias da Próstata , Masculino , Humanos , DNA Tumoral Circulante/genética , Mutação , Neoplasias da Próstata/genética , Ácidos Nucleicos Livres/genética , Perfilação da Expressão Gênica , Biomarcadores Tumorais/genética
19.
Int J Surg ; 109(9): 2721-2731, 2023 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-37247014

RESUMO

BACKGROUND: Post-traumatic related limb osteomyelitis (PTRLO) is a complex bone infection. Currently, there are no available microbial data on a national scale that can guide appropriate antibiotic selection, and explore the dynamic changes in dominant pathogens over time. This study aimed to conduct a comprehensive epidemiological analysis of PTRLO in China. METHODS: The study was approved by the Institutional Research Board (IRB), and 3526 PTRLO patients were identified from 212 394 traumatic limb fracture patients at 21 hospitals between 1 January 2008 and 31 December 2017. A retrospective analysis was conducted to investigate the epidemiology of PTRLO, including changes in infection rate (IR), pathogens, infection risk factors and antibiotic resistance and sensitivity. RESULTS: The IR of PTRLO increased gradually from 0.93 to 2.16% (Z=14.392, P <0.001). Monomicrobial infection (82.6%) was significantly higher than polymicrobial infection (17.4%) ( P <0.001). The IR of Gram-positive (GP) and Gram-negative (GN) pathogens showed a significant increase from the lowest 0.41% to the highest 1.15% (GP) or 1.62% (GN), respectively. However, the longitudinal trend of GP vs. GN's composition did not show any significance (Z=±1.1918, P >0.05). The most prevalent GP strains were Methicillin-sensitive Staphylococcus aureus (MSSA) (17.03%), Methicillin-resistant Staphylococcus aureus (MRSA) (10.46%), E. faecalis (5.19%) and S. epidermidis (4.87%). In contrast, the dominant strains GN strains were Pseudomonas Aeruginosa (10.92%), E. cloacae (10.34%), E. coli (9.47%), Acinetobacter Baumannii (7.92%) and Klebsiella Pneumoniae (3.33%). In general, the high-risk factors for polymicrobial infection include opened-fracture (odds ratio, 2.223), hypoproteinemia (odds ratio, 2.328), and multiple fractures (odds ratio, 1.465). It is important to note that the antibiotics resistance and sensitivity analysis of the pathogens may be influenced by complications or comorbidities. CONCLUSIONS: This study provides the latest data of PTRLO in China and offers trustworthy guidelines for clinical practice. (China Clinical Trials.gov number, ChiCTR1800017597).


Assuntos
Coinfecção , Fraturas Expostas , Staphylococcus aureus Resistente à Meticilina , Osteomielite , Humanos , Estudos Retrospectivos , Escherichia coli , Coinfecção/tratamento farmacológico , Testes de Sensibilidade Microbiana , Antibacterianos/uso terapêutico , China/epidemiologia , Osteomielite/epidemiologia , Osteomielite/etiologia , Osteomielite/tratamento farmacológico
20.
Beijing Da Xue Xue Bao Yi Xue Ban ; 55(2): 283-291, 2023 Apr 18.
Artigo em Chinês | MEDLINE | ID: mdl-37042139

RESUMO

OBJECTIVE: To characterize the paraspinal muscles of adolescent idiopathic scoliosis (AIS) patients, and to further explore its etiology. METHODS: Clinical records and paraspinal muscle biopsies at the apex vertebra region during posterior scoliosis correction surgery of 18 AIS were collected from November 2018 to August 2019. Following standardized processing of fresh muscle tissue biopsy, serial sections with conventional hematoxylin-eosin (HE) and histochemical and immunohistochemical (IHC) with antibody Dystrophin-1 (R-domain), Dystrophin-2 (C-terminal), Dystrophin-3 (N-terminal), Dystrophin-total, Myosin (fast), major histocompatibility complex 1 (MHC-1), CD4, CD8, CD20, and CD68 staining were obtained. Biopsy samples were grouped according to the subjects' median Cobb angle (Cobb angle ≥ 55° as severe AIS group and Cobb angle < 55° as mild AIS group) and Nash-Moe's classification respectively, and the corresponding pathological changes were compared between the groups statistically. RESULTS: Among the 18 AIS patients, 8 were in the severe AIS group (Cobb angle ≥55°) and 10 in the mild AIS group (Cobb angle < 55°). Both severe and mild AIS groups presented various of atrophy and degeneration of paraspinal muscles, varying degrees and staining patterns of immune-expression of Dystrophin-3 loss, especially Dystrophin-2 loss in severe AIS group with significant differences, as well as among the Nash-Moe classification subgroups. Besides, infiltration of CD4+ and CD8+ cells in the paraspinal muscles and tendons was observed in all the patients while CD20+ cells were null. The expression of MHC-1 on myolemma was present in some muscle fibers. CONCLUSION: The histologic of paraspinal muscle biopsy in AIS had similar characteristic changes, the expression of Dystrophin protein was significantly reduced and correlated with the severity of scoliosis, suggesting that Dystrophin protein dysfunctions might contribute to the development of scoliosis. Meanwhile, the inflammatory changes of AIS were mainly manifested by T cell infiltration, and there seemed to be a certain correlation between inflammatory cell infiltration, MHC-1 expression and abnormal expression of Dystrophin. Further research along the lines of this result may open up new ideas for the diagnosis of scoliosis and the treatment of paraspinal myopathy.


Assuntos
Cifose , Hepatopatia Gordurosa não Alcoólica , Escoliose , Humanos , Adolescente , Escoliose/cirurgia , Músculos Paraespinais/metabolismo , Músculos Paraespinais/patologia , Distrofina , Hepatopatia Gordurosa não Alcoólica/patologia , Cifose/patologia , Biópsia
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