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Type 2C protein phosphatases (PP2Cs) constitute a large family in most plant species but relatively few of them have been implicated in immunity. To identify and characterize PP2C phosphatases that affect tomato (Solanum lycopersicum) immunity, we used CRISPR/Cas9 to generate loss-of-function mutations in 11 PP2C-encoding genes whose expression is altered in response to immune elicitors or pathogens. We report that two closely related PP2C phosphatases, Pic3 (PP2C immunity-associated candidate 3) and Pic12, are involved in regulating resistance to the bacterial pathogen Pseudomonas syringae pv. tomato (Pst). Loss-of-function mutations in Pic3 led to enhanced resistance to Pst in older but not younger leaves, whereas such mutations in Pic12 resulted in enhanced resistance in both older and younger leaves. Overexpression of Pic3 and Pic12 proteins in leaves of Nicotiana benthamiana inhibited resistance to Pst, and this effect was dependent on Pic3/12 phosphatase activity and an N-terminal palmitoylation motif associated with localization to the cell periphery. Pic3, but not Pic12, had a slight negative effect on flagellin-associated reactive oxygen species generation, although their involvement in the response to Pst appeared independent of flagellin. RNA-sequencing analysis of Rio Grande (RG)-PtoR wild-type plants and two independent RG-pic3 mutants revealed that the enhanced disease resistance in RG-pic3 older leaves is associated with increased transcript abundance of multiple defense related genes. RG-pic3/RG-pic12 double mutant plants exhibited stronger disease resistance than RG-pic3 or RG-pic12 single mutants. Together, our results reveal that Pic3 and Pic12 negatively regulate tomato immunity in an additive manner through flagellin-independent pathways.
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While adenomyosis is commonly associated with a mild risk of thrombotic complications, the presence of additional thrombophilia factors can increase this risk, particularly in individuals with severe symptoms and elevated CA125 levels.
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The pre BCR complex plays a crucial role in B cell production, and its successful expression marks the B cell differentiation from the pro-B to pre-B. The CD79a and CD79b mutations, encoding Igα and Igß respectively, have been identified as the cause of autosomal recessive agammaglobulinemia (ARA). Here, we present a case of a patient with a homozygous CD79a mutation, exhibiting recurrent respiratory infections, diarrhea, growth and development delay, unique facial abnormalities and microcephaly, as well as neurological symptoms including tethered spinal cord, sacral canal cyst, and chronic enteroviral E18 meningitis. Complete blockade of the early B cell development in the bone marrow of the patient results in the absence of peripheral circulating mature B cells. Whole exome sequencing revealed a Loss of Heterozygosity (LOH) of approximately 19.20Mb containing CD79a on chromosome 19 in the patient. This is the first case of a homozygous CD79a mutation caused by segmental uniparental diploid (UPD). Another key outcome of this study is the effective management of long-term chronic enteroviral meningitis using a combination of intravenous immunoglobulin (IVIG) and fluoxetine. This approach offers compelling evidence of fluoxetine's utility in treating enteroviral meningitis, particularly in immunocompromised patients.
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Agamaglobulinemia , Cromossomos Humanos Par 19 , Fluoxetina , Dissomia Uniparental , Humanos , Fluoxetina/uso terapêutico , Cromossomos Humanos Par 19/genética , Agamaglobulinemia/genética , Agamaglobulinemia/tratamento farmacológico , Antígenos CD79/genética , Masculino , Infecções por Enterovirus/tratamento farmacológico , Infecções por Enterovirus/genética , Mutação/genética , Imunoglobulinas Intravenosas/uso terapêutico , FemininoRESUMO
BACKGROUND: Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) is caused by UNC13D variants. The clinical manifestations of FHL3 are highly diverse and complex. Some patients exhibit atypical or incomplete phenotypes, making accurate diagnosis difficult. Our study aimed to broaden the understanding of the atypical FHL3 clinical spectrum. METHODS: In our study, we analyzed in detail the clinical features of four Chinese patients with UNC13D variants. Additionally, we conducted a comprehensive review of the existing literature on previously reported atypical manifestations and summarized the findings. RESULTS: Two of our patients presented with muscle involvement, while the other two had hematological involvement; none of them met the diagnostic criteria for hemophagocytic lymphohistiocytosis (HLH). However, protein expression and functional analysis ultimately confirmed diagnostic criteria for FHL3 in all patients. From the literature we reviewed, many atypical FHL3 patients had neurological involvement, especially isolated neurological manifestations. At the same time, arthritis and hypogammaglobulinemia were also prone to occur. CONCLUSION: Our study highlights that the expression of the Munc13-4 protein may not fully indicate the pathogenicity of UNC13D variants, whereas CD107a analysis could be more sensitive for disease diagnosis. These findings contribute to a broader understanding of the FHL3 clinical spectrum and may offer new insights into the underlying pathogenesis of UNC13D variants. It is crucial to prioritize the timely and accurate diagnosis of atypical patients, as they may often be overlooked among individuals with rheumatic or hematological diseases.
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Linfo-Histiocitose Hemofagocítica , Proteínas de Membrana , Criança , Feminino , Humanos , Lactente , Masculino , China/epidemiologia , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/genética , Proteínas de Membrana/genética , Mutação , Fenótipo , AdolescenteRESUMO
BACKGROUND: Deleterious BRCA1/2 (BRCA) mutation raises the risk for BRCA mutation-related malignancies, including breast, ovarian, prostate, and pancreatic cancer. Germline variation of BRCA exhibits substantial ethnical diversity. However, there is limited research on the Chinese Han population, constraining the development of strategies for BRCA mutation screening in this large ethnic group. METHODS: We profile the BRCA mutational spectrum, including single nucleotide variation, insertion/deletion, and large genomic rearrangements in 2,080 apparently healthy Chinese Han individuals and 522 patients with BRCA mutation-related cancer, to determine the BRCA genetic background of the Chinese Han population, especially of the East Han. Incident cancer events were monitored in 1,005 participants from the healthy group, comprising 11 BRCA pathogenic/likely pathogenic (PLP) variant carriers and 994 PLP-free individuals, including 3 LGR carriers. RESULTS: Healthy Chinese Han individuals demonstrated a distinct BRCA mutational spectrum compared to cancer patients, with a 0.53% (1 in 189) prevalence of pathogenic/likely pathogenic (PLP) variant, alongside a 3 in 2,080 occurrence of LGR. BRCA1 c. 5470_5477del demonstrated high prevalence (0.44%) in the North Han Chinese and penetrance for breast cancer. None of the 3 LGR carriers developed cancer during the follow-up. We calculated a relative risk of 135.55 (95% CI 25.07 to 732.88) for the development of BRCA mutation-related cancers in the BRCA PLP variant carriers (mean age 42.91 years, median follow-up 10 months) compared to PLP-free individuals (mean age 48.47 years, median follow-up 16 months). CONCLUSION: The unique BRCA mutational profile in the Chinese Han highlights the potential for standardized population-based BRCA variant screening to enhance BRCA mutation-related cancer prevention and treatment.
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Proteína BRCA1 , Neoplasias da Mama , Masculino , Humanos , Adulto , Pessoa de Meia-Idade , Proteína BRCA1/genética , Mutação em Linhagem Germinativa , Proteína BRCA2/genética , Predisposição Genética para Doença , Detecção Precoce de Câncer , China/epidemiologia , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , MutaçãoRESUMO
Early-stage infective endocarditis (IE) can lead to severe complications, including infarctions and metastatic infections caused by inflammatory embolus shedding. Common embolism sites include the brain, spleen, kidneys, lungs, and intestines. Additionally, acute heart failure (AHF) can occur in up to 40% of cases, and its presence can impact the clinical outcomes of patients with IE. Cardiogenic shock (CGS) is often more likely to occur after AHF has taken place. If bacteria invade the blood, infectious shock can occur. Patients with IE can experience simple CGS, septic shock, or a combination of the two. Extracorporeal membrane oxygenation (ECMO) typically serves as a Bridge for Heart failure and Cardiogenic shock. Previous research indicates that there are limited reports of ECMO support for patients with IE after CGS has occurred. Because CGS may occur at any time during IE treatment, it is important to understand the timing of ECMO auxiliary support and how to carry out comprehensive treatment after support. Timely treatment can help to reduce or avoid the occurrence of serious complications and improve the prognosis of patients with IE. Our work combines a case study to review the ECMO support of IE patients after CGS through a literature review. Overall, we suggest that when patients with IE have large bacterial thrombosis and a greater risk of shedding, it is recommended to carefully evaluate the indications and contraindications for ECMO after discussion by a multidisciplinary team (MDT). Still, active surgical treatment at an early stage is recommended.
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Background: Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent malignant cancer worldwide. The cysteine X cysteine (CXC) chemokine family contains 17 members, which are reportedly crucial for the growth, invasion, metastasis, and microenvironment of tumor cells. Although the precise functions of CXC ligands (CXCLs) in HNSCC are unclear, these proteins may play important roles in controlling tumor growth and forming the tumor immune environment. Methods: We downloaded the RNA sequencing and matched clinicopathological data of 379 patients with HNSCC as the training set from The Cancer Genome Atlas and two datasets from the Gene Expression Omnibus for use as validation sets. Results: Through consensus clustering, we identified two subtypes of HNSCC associated with the CXCL family, named cluster1 and cluster2. Patients with the cluster1 subtype showed favourable clinical outcomes, significant immune cell infiltration, and improved immune response signalling pathway modulation. We also developed a nomogram of CXCL family scores for therapeutic use and for predicting the overall survival (OS) of patients with HNSCC. Patients with lower scores showed longer OS and higher immune cell infiltration in their tissues. Conclusions: We developed a new classification method for HNSCC using the CXCL gene family, which can be used clinically to evaluate the prognosis and response to immunotherapy in patients with HNSCC.
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To investigate the incidence, characteristics and risk factors for hypoactive delirium in patients with nontraumatic acute respiratory distress syndrome (ARDS) and to explore the independent risk factors associated with hypoactive delirium and provide new ideas for early prediction and treatment. Hypoactive delirium is a known serious complication in ARDS patients, and currently, there are no effective early detection models or clinical prediction tools, and there is a lack of clinical treatment. This study included nontraumatic ARDS patients who stayed in the intensive care unit (ICU) for more than 24 h and were older than 18 years. A total of 205 ARDS patients admitted to the ICU of Gansu Provincial People's Hospital between December 2021 and February 2023 were selected. Demographic data, clinical characteristics and laboratory test results were collected within 24 h after the patients entered the ICU. Multivariate logistic regression analysis was used to investigate risk factors, evaluate the clinical prediction effect of the model and construct a nomogram for visual display. The incidence of hypoactive delirium among the patients included in the study was 41%. Patients with hypoactive delirium had hypertension; diabetes mellitus; Acute Physiology and Chronic Health Evaluation II (APACHE II) scores ≥ 15; and increased procalcitonin, C-reactive protein (CRP), lactic dehydrogenase and interleukin-6 (IL-6) levels compared with those without hypoactive delirium. Logistic regression analysis revealed that diabetes mellitus (OR 3.305, 95% CI: 1.866-12.616; p = 0.047), CRP level (OR 1.002, 95% CI: 1.001-1.023; p = 0.044), and IL-6 level (OR 1.045, 95% CI: 1.017-1.063; p = 0.001) were independent risk factors for hypoactive delirium. After receiver operating characteristic (ROC) curve analysis, calibration plot and decision curve analysis (DCA) confirmed that the clinical prediction ability of this study model was satisfactory, and a nomogram was drawn for visual display. Hypoactive delirium is a common serious complication in nontraumatic ARDS patients. Our logistic regression model not only effectively predicts hypoactive delirium early but also reveals potential clinical therapeutic targets.
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Delírio , Diabetes Mellitus , Síndrome do Desconforto Respiratório , Humanos , Interleucina-6 , Síndrome do Desconforto Respiratório/complicações , Síndrome do Desconforto Respiratório/terapia , Unidades de Terapia Intensiva , Fatores de Risco , Hipocinesia , Delírio/epidemiologia , Delírio/etiologia , Delírio/diagnóstico , Estudos RetrospectivosRESUMO
ABSTRACT: The objective of this academic research is to assess the efficacy of conventional endorectal ultrasound (ERUS), ultrasonic shear wave elastography (SWE), and magnetic resonance imaging (MRI) techniques in evaluating the impact of neoadjuvant therapy (nCRT). Forty-five patients with advanced low rectal cancer (T ≥ 3) were included. Before and after nCRT, ERUS, SWE, and MRI evaluations were conducted. The T staging of ultrasound (uT) and MRI (mT) were evaluated and compared with the pathological T staging (ypT). The accuracy of the 2 diagnostic methods for T staging, and T downstaging was evaluated. The ultrasound elasticity difference and relative elasticity before and after treatment and pathological T downstaging were compared, and its cutoff value and the area under the curve were assessed. In terms of T staging accuracy after chemoradiotherapy, the values for ERUS, ERUS combined with SWE, and MRI were 64.4%, 71.1%, and 62.2%, respectively. No significant difference was observed among these groups ( P > 0.05). The accuracy of uT downstaging was 84.4%, and that of mT downstaging was 88.9%. The receiver operating characteristic curve of uLD and elastic differences and relative elasticity of T downstaging after treatment were 0.754, 0.817, and 0.886, respectively (all P < 0.05). Both ERUS and MRI can evaluate ypT downstaging. The indicators for evaluating T downstaging are uLD, elasticity difference, and relative elasticity, providing more reference for clinical assessment of nCRT efficacy.
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Técnicas de Imagem por Elasticidade , Endossonografia , Imageamento por Ressonância Magnética , Terapia Neoadjuvante , Estadiamento de Neoplasias , Neoplasias Retais , Humanos , Neoplasias Retais/diagnóstico por imagem , Neoplasias Retais/terapia , Neoplasias Retais/patologia , Técnicas de Imagem por Elasticidade/métodos , Terapia Neoadjuvante/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Imageamento por Ressonância Magnética/métodos , Endossonografia/métodos , Idoso , Reprodutibilidade dos Testes , Adulto , Reto/diagnóstico por imagem , Resultado do TratamentoRESUMO
Ethephon (ETH), a commonly employed growth regulator, poses potential health risks due to its residue in fruits and vegetables, leading to both acute and subchronic toxicity. However, the detection accuracy of ETH is compromised by the color effects of the samples during the detection process. In this work, a multienzyme reaction-mediated electrochemical biosensor (MRMEC) was developed for the sensitive, rapid, and color-interference-resistant determination of ETH. Nanozymes Fe3O4@Au-Pt and graphene nanocomplexes (GN-Au NPs) were prepared as catalysts and signal amplifiers for MRMEC. Acetylcholinesterase (AChE), acetylcholine (ACh), and choline oxidase (CHOx) form a cascade enzyme reaction to produce H2O2 in an electrolytic cell. Fe3O4@Au-Pt has excellent peroxidase-like activity and can catalyze the oxidation of 3,3',5,5'-tetramethvlbenzidine (TMB) in the presence of H2O2, resulting in a decrease in the characteristic peak current of TMB. Based on the inhibitory effect of ETH on AChE, the differential pulse voltammetry (DPV) current signal of TMB was used to detect ETH, offering the limit of detection (LOD) of 2.01 nmol L-1. The MRMEC method effectively analyzed ETH levels in mangoes, showing satisfactory precision (coefficient of variations, 2.88-15.97%) and recovery rate (92.18-110.72%). This biosensor holds promise for detecting various organophosphorus pesticides in food samples.
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Técnicas Biossensoriais , Praguicidas , Praguicidas/química , Compostos Organofosforados , Acetilcolinesterase/química , Peróxido de Hidrogênio/química , Técnicas Biossensoriais/métodosRESUMO
Background: The diagnosis of lung adenocarcinoma (LUAD) leptomeningeal metastasis (LM) remains a clinical challenge. Human epididymis protein 4 (HE4) functions as a novel tumor biomarker for cancers. This study aimed to assess the diagnostic value of cerebrospinal fluid (CSF) HE4, and combined with CEACAM6, for LUAD LM. Methods: The CSF HE4 protein level was measured in two independent cohorts by electrochemiluminescence. Test cohort included 58 LUAD LM patients, 22 LUAD patients without LM (Wiot-LM), and 68 normal controls. Validation cohort enrolled 50 LUAD LM patients and 40 normal controls, in parallel with Wiot-LM patients without brain metastases (19 Wiot-LM/BrM patients) or with BrM (26 BrM patients). The CSF level of CEA, CA125, CA153, CA199, CA724, NSE and ProGRP of these samples was measured by electrochemiluminescence, whereas the CSF CEACAM6 level was detected by enzyme-linked immunosorbent assay (ELISA). In addition, the serum level of these biomarkers was detected by same method as CSF. Results: The level of HE4 or CEACAM6 in CSF samples from LUAD LM patients was significantly higher than those from normal controls and Wiot-LM patients. The HE4 or CEACAM6 level in CSF was higher than that in serum of LM patient. The CSF HE4 or CEACAM6 level for distinguished LM from Wiot-LM showed good performance by receiver-operating characteristic analysis. The better discriminative power for LM was achieved when HE4 was combined with CEACAM6. In addition, the CSF HE4 and CEACAM6 level showed little or no difference between Wiot-LM/BrM and BrM patients, the BrM would not significantly influence the HE4 or CEACAM6 level in CSF. The diagnostic power of CSF CA125, CA153, CA199, CA724, NSE and ProGRP for LUAD LM were not ideal. Conclusion: The combination with HE4 and CEACAM6 has the promising application for the diagnosis of LUAD LM.
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Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Adenocarcinoma de Pulmão/diagnóstico , Biomarcadores Tumorais , Curva ROC , Neoplasias Pulmonares/patologiaRESUMO
Astragaloside IV (AS-IV) has exhibited pivotal anti-cancer efficacy in multiple types of cancer, including colorectal cancer (CRC). Meanwhile, circular RNA (circRNA) circ_0001615 has been reported to be involved in the malignant development of CRC. Herein, this study is expected to figure out the interaction between circ_0001615 and AS-IV on CRC progression. The 50% inhibition concentration (IC50), proliferation, apoptosis, and migration were detected by Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry, and wound healing assays. The expression of related proteins was examined by western blot. Circ_0001615, microRNA-873-5p (miR-873-5p), and LIM and SH3 protein 1 (LASP1) levels were detected by real-time quantitative polymerase chain reaction (RT-qPCR). The binding between miR-873-5p and circ_0001615, or LASP1, was predicted by Starbase, followed by verification by dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. The biological role of circ_0001615 and AS-IV on CRC tumor growth was detected by the xenograft tumor model in vivo. According to the IC50 of AS-IV in CRC cells, the 100 ng/mL AS-IV treatment for 24 h was chosen for the following research: Our data confirmed that AS-IV is a beneficial anti-cancer agent in CRC cells. Furthermore, circ_0001615 and LASP1 expression were increased, and miR-873-5p was decreased in CRC patients and cell lines, whereas their expression exhibited an opposite trend in AS-IV-treated cells. Functionally, applying AS-IV might act as a beneficial anti-cancer effect by downregulating circ_0001615 in CRC cells in vitro. Mechanically, circ_0001615 serves as a sponge for miR-873-5p to affect LASP1 expression. In addition, AS-IV inhibited CRC cell growth in vivo by modulating circ_0001615. Overall, AS-IV could mitigate CRC development, at least in part, through the circ_0001615/miR-873-5p/LASP1 axis. These findings support a theoretical basis for an in-depth study of the function of AS-IV and the clinical treatment of CRC.
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Neoplasias Colorretais , MicroRNAs , Saponinas , Triterpenos , Humanos , Animais , Saponinas/farmacologia , Saponinas/uso terapêutico , Triterpenos/farmacologia , Modelos Animais de Doenças , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , MicroRNAs/genética , Proliferação de Células , Proteínas do Citoesqueleto , Proteínas Adaptadoras de Transdução de Sinal , Proteínas com Domínio LIMRESUMO
OBJECTIVE: Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) are new treatment for advanced non-small cell lung cancer. Here, we quantified the toxicity profiles of different ALK-TKIs to guide clinical decision making. MATERIALS AND METHODS: We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials. Data were analyzed using random effects and consistency models under the frequency framework. RESULTS: Of 865 relevant studies, 13 RCTs (encompassing 3,353 patients) were finally included. A network meta-analysis of all-grade AEs, fatal AEs, and treatment discontinuation due to AEs revealed no significant differences among the six ALK-TKIs. The rates of grade 3-4 AEs were: alectinib (16.2%), crizotinib (46.4%), brigatinib (63.7%), ensartinib (75.6%), ceritinib (78.3%), and lorlatinib (91.6%). The toxicity spectra of ALK-TKIs were different. The most frequent AEs associated with crizotinib were gastrointestinal reactions, visual disorders, neutropenia, edema, fatigue, and elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels, while those in the alectinib group were anemia and constipation. Diarrhea, hepatotoxicity, and increased serum creatinine were most common with ceritinib. The most frequent AEs in the brigatinib group were gastrointestinal reactions, hypertension, cough, headache, and elevated ALT or AST levels. The most significant toxicities of ensartinib were skin disorders, including pruritus and rash. Changes in lipid levels were the most frequent AEs associated with lorlatinib; weight gain, cognitive effects, and mood effects were lorlatinib-specific AEs. CONCLUSIONS: The toxicity spectra of ALK-TKIs differed. Alectinib might be the safest ALK-TKI drug according to the combined evidence of grades 3-4 AEs and the combined incidence.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Quinase do Linfoma Anaplásico/genética , Proteínas Tirosina Quinases , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Crizotinibe , Metanálise em Rede , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Inibidores de Proteínas Quinases/efeitos adversosRESUMO
Nod-like receptor family pyrin domain-containing protein 12 (NLRP12) is one of the critical pattern recognition receptors which participates in the regulation of multiple inflammatory responses. Mutations in NLRP12 cause exceptionally rare NLRP12-associated autoinflammatory disease (NLRP12-AID). So far, very few patients with NLRP12-AID have been identified worldwide; therefore, data on the clinical phenotype and genetic profile are limited. In this study, we reported 10 patients who presented mainly with periodic fever syndrome or arthritis. Next-generation sequencing (NGS) identified 6 heterozygous mutations of NLRP12, including 2 novel null mutations. Of the patients, some with same mutations showed different clinical features. Compared to healthy controls, the increased levels of cytokines were revealed in the patients' plasmas, as well as in the supernatants of patients' cells stimulated with lipopolysaccharide (LPS) or tumor necrosis factor-α (TNF-α). The missense mutations did not change the protein expression; but decreased level of NLRP12 protein was shown in the null mutations. And in vitro expression assay demonstrated a truncating protein induced by the frameshift mutation. Further functional studies revealed the deleterious effect of mutations on nuclear factor-kappa B (NF-κB) signaling. Both the null and missense mutations impaired their inhibition of NF-κB activation induced by p65. Collectively, this study reported a relatively large NLRP12-AID case series. Our findings expand the clinical spectrum, and reinforce the diversity of genetic mutations and clinical phenotypes. The NLRP12-associated disorder should be considered when autoinflammatory diseases are encountered in the clinical practice, especially for patients presenting with periodic fever but no other genetic cause identified.
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Cancer metastasis is a significant challenge in cancer treatment, and most existing drugs are designed to inhibit tumor growth but are often ineffective in treating metastatic cancer, which is the leading cause of cancer-related deaths. Resveratrol, a polyphenol found in grapes, berries, and peanuts, has shown potential in preclinical studies as an anticancer agent to suppress metastasis. However, despite positive results in preclinical studies, little progress has been made in clinical trials. To develop resveratrol as an effective anticancer agent, it is crucial to understand its cellular processes and signaling pathways in tumor metastasis. This review article evaluates the current state and future development strategies of resveratrol to enhance its potency against cancer metastasis within its therapeutic dose. In addition, we critically evaluate the animal models used in preclinical studies for cancer metastasis and discuss novel techniques to accelerate the translation of resveratrol from bench to bedside. The appropriate selection of animal models is vital in determining whether resveratrol can be further developed as an antimetastatic drug in cancer therapy.
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PF-543 is a sphingosine kinase 1ï¼SPHK1ï¼inhibitor developed by Pfizer and is currently considered the most potent selective SPHK1 inhibitor. SPHK1 catalyses the production of sphingosine 1-phosphate (S1P) from sphingosine. It is the rate-limiting enzyme of S1P production, and there is substantial evidence to support a very important role for sphingosine kinase in health and disease. This review is the first to summarize the role and mechanisms of PF-543 as an SPHK1 inhibitor in anticancer, antifibrotic, and anti-inflammatory processes, providing new therapeutic leads and ideas for future research and clinical trials.
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Fosfotransferases (Aceptor do Grupo Álcool) , EsfingosinaRESUMO
Background: Human Parvovirus B19 (PB19) is a single-stranded DNA virus. Septic shock from viremia is rare with PB19; however, this infection can progress to life-threatening conditions. We report the first case of severe septic shock associated with a PB19 infection after cardiac surgery. Case Presentation: A 50-year-old Chinese woman received elective double metal valve replacement, including the aortic valve and the mitral valve, under cardiopulmonary bypass (CPB) and suffered severe septic shock on postoperative day (PD) 30. Through the detection of PB19-specific nucleic acids in blister fluid and serum samples via metagenomic next-generation sequencing (mNGS), positive serum PB19 IgM and no other proven infection, acute PB19 infection was confirmed. After five days of combined treatment, no further fever or abdominal discomfort was noted, and the patient's circulation gradually became stable without vasoactive medications. Conclusion: PB19 may be an unrecognized cause of septic shock, rash, fever of unknown origin or multiple systemic signs and symptoms, especially in immunosuppressed and immunocompetent critically ill patients. Investigations for viral aetiology are needed.
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Procedimentos Cirúrgicos Cardíacos , Eritema Infeccioso , Parvovirus B19 Humano , Choque Séptico , Feminino , Humanos , Pessoa de Meia-Idade , Eritema Infeccioso/complicações , Choque Séptico/etiologia , Choque Séptico/complicações , Parvovirus B19 Humano/genética , Anticorpos AntiviraisRESUMO
Zeta(ζ)-Chain Associated Protein Kinase 70 kDa (ZAP-70) deficiency is a rare autosomal recessive primary immunodeficiency disease. Little is known about this disease. In this study, we report two patients to extend the range of clinical phenotypes and immunophenotypes associated with ZAP-70 mutations. We describe the clinical, genetic, and immunological phenotypes of two patients with ZAP-70 deficiency in China, and the data are also compared with the literature. Case 1 presented with leaky severe combined immunodeficiency with low to the absence of CD8 + T cells, while case 2 suffered from a recurrent respiratory infection and had a past medical history of non-EBV-associated Hodgkin's lymphoma. Sequencing revealed novel compound heterozygous mutations in ZAP-70 of these patients. Case 2 is the second ZAP-70 patient presenting a normal CD8 + T cell number. These two cases have been treated with hematopoietic stem cell transplantation. Selective CD8 + T cell loss is an essential feature of the immunophenotype of ZAP-70 deficiency patients, but there are exceptions. Hematopoietic stem cell transplantation can provide excellent long-term immune function and resolution of clinical problems.
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Linfócitos T CD8-Positivos , Humanos , China , Mutação , FenótipoRESUMO
Purpose: By using a radiomics-based approach, multiple radiomics features can be extracted from regions of interest in computed tomography (CT) images, which may be applied to automatically classify kidney tumors and normal kidney tissues. The study proposes a method based on CT radiomics and aims to use extracted radiomics features to automatically classify of kidney tumors and normal kidney tissues and to establish an automatic classification model. Methods: CT data were retrieved from the 2019 Kidney and Kidney Tumor Segmentation Challenge (KiTS19) in The Cancer Imaging Archive (TCIA) open access database. Arterial phase-enhanced CT images from 210 cases were used to establish an automatic classification model. These CT images of patients were randomly divided into training (168 cases) and test (42 cases) sets. Furthermore, the radiomics features of gross tumor volume (GTV) and normal kidney tissues in the training set were extracted and screened, and a binary logistic regression model was established. For the test set, the radiomic features and cutoff value of P were consistent with the training set. Results: Three radiomics features were selected to establish the binary logistic regression model. The accuracy (ACC), sensitivity (SENS), specificity (SPEC), area under the curve (AUC), and Youden index of the training and test sets based on the CT radiomics classification model were all higher than 0.85. Conclusion: The automatic classification model of kidney tumors and normal kidney tissues based on CT radiomics exhibited good classification ability. Kidney tumors could be distinguished from normal kidney tissues. This study may complement automated tumor delineation techniques and warrants further research.