RESUMO
E3 ubiquitin ligases are very important for regulating antiviral immunity during viral infection. Here, we discovered that Ankyrin repeat and SOCS box-containing protein 3 (ASB3), an E3 ligase, are upregulated in the presence of RNA viruses, particularly influenza A virus (IAV). Notably, overexpression of ASB3 inhibits type I IFN (IFN-I) responses induced by Sendai virus (SeV) and IAV, and ablation of ASB3 restores SeV and H9N2 infection-mediated transcription of IFN-ß and its downstream interferon-stimulated genes (ISGs). Interestingly, animals lacking ASB3 presented decreased susceptibility to H9N2 and H1N1 infections. Mechanistically, ASB3 interacts with MAVS and directly mediates K48-linked polyubiquitination and degradation of MAVS at K297, thereby inhibiting the phosphorylation of TBK1 and IRF3 and downregulating downstream antiviral signaling. These findings establish ASB3 as a critical negative regulator that controls the activation of antiviral signaling and describe a novel function of ASB3 that has not been previously reported.
RESUMO
The problem of paddy Cadmium (Cd) contamination is currently the focus of global research. Earlier researches have confirmed that utilization of organic fertilizers regulates Cd chemical fraction distribution by increases organic bound Cd. However, environmental behaviours of organic fertilizers in paddy are still lack exploration. Here, we critical reviewed previous publications and proposed a novel research concept to help us better understand it. Three potential impact pathways of utilization of organic fertilizers on the bioavailability of Cd are presented: (i) use of organic fertilizers changes soil physicochemical properties, which directly affects Cd bioavailability by changing chemical form of Cd(II); (ii) use of organic fertilizers increases soil nutrient content, which indirectly regulates Cd supply and bioaccumulation through ion adsorption and competition for ion-transport channels between nutrients and Cd; and (iii) use of organic fertilizers increases activity of microorganisms and efflux of rice root exudates, which indirectly affects Cd bioavailability of through complexation and sequestration of these organic materials with Cd. Meanwhile, dissolved organic matter (DOM) in the rhizosphere of rice is believed to be the key to revealing the effects of organic fertilizers on Cd. DOM is capable of adsorption and complexation-chelation reactions with Cd and the fractionation of Cd(II) is regulated by DOM. Molecular mass, chemical composition, major functional groups and reaction sequence of DOM determine the formation and solubilization of DOM-Cd complexes.
RESUMO
N-acetyl-D-glucosamine and its dimer are degradation products of chitin waste with great potential in therapeutic and agricultural applications. However, the hydrolysis of insoluble chitin by chitinases remains a major bottleneck. This study investigated the biochemical properties and catalytic mechanisms of PoChi chitinase obtained from Penicillium oxalicum with a focus on enhancing its efficiency during the degradation of insoluble chitin. Recombinant plasmids were engineered to incorporate chitin-binding (ChBD) and/or fibronectin III (FnIII) domains. Notably, PoChi-FnIII-ChBD exhibited the highest substrate affinity (Km = 2.7 mg/mL) and a specific activity of 15.4 U/mg, which surpasses those of previously reported chitinases. These findings highlight the potential of engineered chitinases in advancing industrial biotechnology applications and offer a promising approach to more sustainable chitin waste management.
Assuntos
Quitina , Quitinases , Penicillium , Quitinases/metabolismo , Quitinases/genética , Quitina/metabolismo , Penicillium/enzimologia , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Recombinantes de Fusão/genética , Hidrólise , Engenharia de Proteínas/métodos , Solubilidade , CinéticaRESUMO
OBJECTIVES: We explored Trichorhinophalangeal syndrome type 1 (TRPS1) expression in special types of breast carcinoma, and analyzed the correlation between TRPS1 and androgen receptor (AR) expression in triple-negative breast cancer (TNBC). METHODS: TRPS1 expression was analyzed in 801 patients with special types of breast carcinoma. A total of 969 TNBC were used to analyze the correlation between the expression of TRPS1 and AR. TRPS1 expression was evaluated in 1975 cases of breast cancer with different molecular types. RESULTS: A total of 801 special types of breast cancers were stained with TRPS1.TRPS1 was positive in 100% (63/63) of mucinous carcinoma, 100% (7/7) adenoid cystic carcinomas (4 classic adenoid cystic carcinomas and 3 solid-basaloid adenoid cystic carcinomas), 100% (4/4) tubular carcinomas, 100% (2/2) secretory carcinomas, and 99.59% (243/244) invasive lobular carcinomas, 99.26% (267/269) invasive micropapillary carcinomas, 97.44% (38/39) ER-positive neuroendocrine tumors, 94.44% (34/36) metaplastic breast carcinomas (MBCs), 63.73% (65/102) apocrine carcinomas. TRPS1 was negative in all triple-negative neuroendocrine carcinomas (0/7).TRPS1 was positive in 92.86% (26/28) of metastatic special types of breast cancer. TRPS1 and AR expression were analyzed in 969 cases of TNBC. 90.40% were positive for TRPS1, and 42.41% were positive for AR. A significant inverse correlation between TRPS1 and AR expression was shown in TNBC (p < .001). TRPS1 showed a higher positive rate (93.13%) in TNBC compared to GATA binding protein 3 (GATA3), gross cystic disease fluid protein 15 (GCDFP-15) and forkhead box transcription Factor C 1 (FOXC1). CONCLUSIONS: In conclusion, our study demonstrated that TRPS1 is a highly sensitive marker for most special types of breast carcinoma. TRPS1 was positive in 63.73% of apocrine carcinomas. TRPS1 and AR expression was inversely correlated in TNBC.
Assuntos
Biomarcadores Tumorais , Proteínas de Ligação a DNA , Receptores Androgênicos , Proteínas Repressoras , Fatores de Transcrição , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Biomarcadores Tumorais/análise , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/genética , Proteínas Repressoras/análise , Proteínas de Ligação a DNA/análise , Proteínas de Ligação a DNA/metabolismo , Fatores de Transcrição/análise , Receptores Androgênicos/análise , Receptores Androgênicos/genética , Imuno-Histoquímica , Pessoa de Meia-Idade , Neoplasias da Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , AdultoRESUMO
Background: The composition of the gut microbiome has been recorted to be strongly associated with gestational diabetes mellitus (GDM), but mutational characterization of the microbiome in patients with GDM has been overlooked. Here, we revealed the genetic variation landscape of the gut microbiome and assessed its clinical significance in a cohort of patients with GDM. Methods: We employed a macrogenomic dataset made up of a discovery cohort of 54 cases and a validation cohort of 220 cases to screen for high-abundance microbial flora and identified single nucleotide variants (SNVs) and insertions/deletions (indels). Subsequently, we analyzed the mutation spectra of genomes of the intestinal flora by using the previously identified SNVs and identified mutation signatures. Additionally, we utilized the Random Forest algorithm to identify key differential SNVs and elucidated their biological functions and associations with the clinicopathological parameters of GDM. Results: We screened 15 key microbial flora and found that the GDM group had more SNVs and indels in the intestinal flora than the control group, with a significant increase in C > T and T > C base mutations and were more susceptible to sequence mutations. Compared to the control group, the GDM group underwent a more significant evolution, as evidenced by the presence of a unique mutational spectrum and mutational characteristics. Random Forest algorithm analysis showed that the combined characterization of five gut microbial species and 21 SNV-related markers was effective in distinguishing between GDM and control subjects in both discovery (area under the curve (AUC) = 0.86) and validation (AUC = 0.73) sets. These markers also revealed that GDM is strongly associated with sphingolipids, galactose, and proteins containing the DUF structural domain. Conclusions: The GDM intestinal flora has unique mutational features that correlate significantly with clinicopathological involvement and may be involved in the development of the disease.
RESUMO
Programmed cell death (PCD) is a fundamental biological process for maintaining cellular equilibrium and regulating development, health, and disease across all living organisms. Among the various types of PCD, apoptosis plays a pivotal role in numerous diseases, notably cancer. Cancer cells frequently develop mechanisms to evade apoptosis, increasing resistance to standard chemotherapy treatments. This resistance has prompted extensive research into alternative mechanisms of programmed cell death. One such pathway is oncosis, characterized by significant energy consumption, cell swelling, dilation of the endoplasmic reticulum, mitochondrial swelling, and nuclear chromatin aggregation. Recent research suggests that oncosis can impact conditions such as chemotherapeutic cardiotoxicity, myocardial ischemic injury, stroke, and cancer, mediated by specific oncosis-related proteins. In this review, we provide a detailed examination of the morphological and molecular features of oncosis and discuss various natural or small molecule compounds that can induce this type of cell death. Additionally, we summarize the current understanding of the molecular mechanisms underlying oncosis and its role in both normal physiology and pathological conditions. These insights aim to illuminate future research directions and propose innovative strategies for leveraging oncosis as a therapeutic tool against human diseases and cancer resistance.
Assuntos
Apoptose , Neoplasias , Humanos , Neoplasias/patologia , Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Animais , Transdução de Sinais , Morte Celular , Mitocôndrias/metabolismoRESUMO
BACKGROUND AND AIMS: Hexokinases (HKs), a group of enzymes catalyzing the first step of glycolysis, have been shown to play important roles in liver metabolism and tumorigenesis. Our recent studies identified HKDC1 as a top candidate associated with liver cancer metastasis. We aimed to compare its cell type specificity with other HKs upregulated in liver cancer and investigate the molecular mechanisms underlying its involvement in liver cancer metastasis. APPROACH AND RESULTS: We found that, compared to HK1 and HK2, the other two commonly upregulated HKs in liver cancer, HKDC1 was most strongly associated with the metastasis potential of tumors and organoids derived from two liver cancer mouse models we previously established. RNA in situ hybridization and single-cell RNA-seq analysis revealed that HKDC1 was specifically upregulated in malignant cells in hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) patient tumors, whereas HK1 and HK2 were widespread across various tumor microenvironment lineages. An unbiased metabolomic profiling demonstrated that HKDC1 overexpression in HCC cells led to metabolic alterations distinct from those from HK1 and HK2 overexpression, with HKDC1 particularly impacting the tricarboxylic acid (TCA) cycle. HKDC1 was prometastatic in HCC orthotopic and tail vein injection mouse models. Molecularly, HKDC1 was induced by hypoxia and bound to glycogen synthase kinase 3ß to stabilize ß-catenin, leading to enhanced stemness of HCC cells. CONCLUSIONS: Overall, our findings underscore HKDC1 as a prometastatic HK specifically expressed in the malignant compartment of primary liver tumors, thereby providing a mechanistic basis for targeting this enzyme in advanced liver cancer.
RESUMO
Clinical trials have demonstrated conclusively the non-inferiority of breast-conserving surgery followed by breast radiation therapy (BCT) compared with mastectomy for the treatment of early-stage invasive breast cancer (BC). The definition of the required surgical margin to ensure adequate removal of the cancer by BCT to obtain an acceptable low local recurrence (LR) rate remains controversial. Meta-analyses published by Houssami et al. in 2010 and 2014 demonstrated significantly lower LR rates for patients with a negative margin compared with those with positive (ink on tumour) or close (defined as ≤1 mm or ≤2 mm) margins. Neither meta-analysis addressed whether 'no ink on tumour' was adequate to define a negative margin because of a lack of data. Nevertheless, in 2014, the Society of Surgical Oncology (SSO) and the American Society for Radiation Oncology (ASTRO) with advice from pathologists reviewed these data together and published guidelines recommending that a margin of 'no ink on tumour' was sufficient to define a clear margin in BCT. Subsequently, clinical practice has varied with some national and international bodies endorsing 'no ink on tumour', whilst others have recommended a ≥1 mm margin as acceptable margins for BCT. A more recent meta-analysis conducted by Bundred and colleagues in 2022 did have sufficient data to compare 'no ink on tumour' and 1 mm and concluded that 1 mm rather than 'no ink on tumour', should be used as a minimum negative margin, and recommended that international guidelines be revised. The current review presents a balanced assessment of the evidence relating margin width and local recurrence after BCT. This review concludes that guidelines should consider re-defining a negative margin as ≥1 mm rather than 'no ink on tumour' in the context of BCT, recognising there will be variation to tailor therapy for any individual patient situation to ensure optimal patient care.
Assuntos
Neoplasias da Mama , Margens de Excisão , Mastectomia Segmentar , Recidiva Local de Neoplasia , Humanos , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Neoplasias da Mama/radioterapia , Mastectomia Segmentar/métodos , Feminino , Recidiva Local de Neoplasia/patologia , Invasividade NeoplásicaRESUMO
The functions of the natural dsRNA sensors TLR3 (TRIF) and RIG-I (MAVS) are crucial during viral challenge and have not been accurately clarified in adaptive immune responses to rotavirus (RV) infection. In this study, we found that RV infection caused severe pathological damage to the small intestine of TLR3-/- and TRIF-/- mice. Our data found that dendritic cells from TLR3-/- and TRIF-/- mice had impaired Ag presentation to the RV and attenuated initiation of T cells upon viral infection. These attenuated functions resulted in impaired CD4+ T and CD8+ T function in mice lacking TLR3-TRIF signaling postinfection. Additionally, attenuated proliferative capacity of T cells from TLR3-/- and TRIF-/- mice was observed. Subsequently, we observed a significant reduction in the absolute number of memory T cells in the spleen and mesenteric lymph node (MLN) of TRIF-/- recipient mice following RV infection in a bone marrow chimeric model. Furthermore, there was reduced migration of type 2 classical dendritic cells from the intestine to MLNs after RV infection in TLR3-/- and TRIF-/- mice. Notably, RV infection resulted in attenuated killing of spleen and MLN tissues in TRIF-/- and MAVS-/- mice. Finally, we demonstrated that RV infection promoted apoptosis of CD8+ T cells in TRIF-/- and TLR3-/-MAVS-/- mice. Taken together, our findings highlight an important mechanism of TLR3 signaling through TRIF in mucosal T cell responses to RV and lay the foundation for the development of a novel vaccine.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Proteínas Adaptadoras de Transporte Vesicular , Células Dendríticas , Camundongos Knockout , Infecções por Rotavirus , Rotavirus , Transdução de Sinais , Receptor 3 Toll-Like , Animais , Receptor 3 Toll-Like/imunologia , Camundongos , Infecções por Rotavirus/imunologia , Transdução de Sinais/imunologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Rotavirus/imunologia , Células Dendríticas/imunologia , Camundongos Endogâmicos C57BL , Mucosa Intestinal/imunologia , Linfócitos T CD8-Positivos/imunologia , Imunidade nas Mucosas , Apresentação de Antígeno/imunologiaRESUMO
E3 ubiquitin ligase (E3) plays a vital role in regulating inflammatory responses by mediating ubiquitination. Previous studies have shown that ankyrin repeat and SOCS box-containing protein 3 (ASB3) is involved in immunomodulatory functions associated with cancer. However, the impact of ASB3 on the dynamic interplay of microbiota and inflammatory responses in inflammatory bowel disease (IBD) is unclear. Here, we systematically identify the E3 ligase ASB3 as a facilitative regulator in the development and progression of IBD. We observed that ASB3 exhibited significant upregulation in the lesions of patients with IBD. ASB3-/- mice are resistant to dextran sodium sulfate-induced colitis. IκBα phosphorylation levels and production of proinflammatory factors IL-1ß, IL-6, and TNF-α were reduced in the colonic tissues of ASB3-/- mice compared to WT mice. This colitis-resistant phenotype was suppressed after coprophagic microbial transfer and reversed after combined antibiotics removed the gut commensal microbiome. Mechanistically, ASB3 specifically catalyzes K48-linked polyubiquitination of TRAF6 in intestinal epithelial cells. In contrast, in ASB3-deficient organoids, the integrity of the TRAF6 protein is shielded, consequently decelerating the onset of intestinal inflammation. ASB3 is associated with dysregulation of the colitis microbiota and promotes proinflammatory factors' production by disrupting TRAF6 stability. Strategies to limit the protein level of ASB3 in intestinal epithelial cells may help in the treatment of colitis. IMPORTANCE: Ubiquitination is a key process that controls protein stability. We determined the ubiquitination of TRAF6 by ASB3 in intestinal epithelial cells during colonic inflammation. Inflammatory bowel disease patients exhibit upregulated ASB3 expression at focal sites, supporting the involvement of degradation of TRAF6, which promotes TLR-Myd88/TRIF-independent NF-κB aberrant activation and intestinal microbiota imbalance. Sustained inflammatory signaling in intestinal epithelial cells and dysregulated protective probiotic immune responses mediated by ASB3 collectively contribute to the exacerbation of inflammatory bowel disease. These findings provide insights into the pathogenesis of inflammatory bowel disease and suggest a novel mechanism by which ASB3 increases the risk of colitis. Our results suggest that future inhibition of ASB3 in intestinal epithelial cells may be a novel clinical strategy.
Assuntos
Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Camundongos Knockout , Fator 6 Associado a Receptor de TNF , Animais , Humanos , Camundongos , Colite/microbiologia , Colite/induzido quimicamente , Colite/genética , Colite/metabolismo , Modelos Animais de Doenças , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/imunologia , Camundongos Endogâmicos C57BL , Estabilidade Proteica , Proteínas Supressoras da Sinalização de Citocina/genética , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Fator 6 Associado a Receptor de TNF/metabolismo , Fator 6 Associado a Receptor de TNF/genética , UbiquitinaçãoRESUMO
BACKGROUND: Concomitant Wilms tumor (WT) and autosomal dominant polycystic kidney disease (ADPKD) is exceedingly rare, presenting a diagnostic and technical challenge to pediatric surgical oncologists. The simultaneous workup and management of these disease processes are incompletely described. PROCEDURE: We performed a retrospective analysis of patients treated at our institution with concomitant diagnoses of WT and ADPKD. We also review the literature on the underlying biology and management principles of these conditions. RESULTS: We present three diverse cases of concomitant unilateral WT and ADPKD who underwent nephrectomy. One patient had preoperative imaging consistent with ADPKD with confirmatory testing postoperatively, one was found to have contralateral renal cysts intraoperatively with confirmatory imaging post nephrectomy, and one was diagnosed in childhood post nephrectomy. All patients are alive at last follow-up, and the patient with longest follow-up has progressed to end-stage kidney failure requiring transplantation and dialysis in adulthood. All patients underwent germline testing and were found to have no cancer predisposition syndrome or pathogenic or likely pathogenic variants for WT. CONCLUSION: Concomitant inheritance of ADPKD and development of WT are extremely rare, and manifestations of ADPKD may not present until late childhood or adulthood. ADPKD is not a known predisposing condition for WT. When ADPKD diagnosis is made by family history, imaging, and/or genetic testing before WT diagnosis and treatment, the need for extensive preoperative characterization of cystic kidney lesions in children and increased risk of post-nephrectomy kidney failure warrant further discussion of surgical approach and perioperative management strategies.
Assuntos
Neoplasias Renais , Rim Policístico Autossômico Dominante , Tumor de Wilms , Pré-Escolar , Feminino , Humanos , Masculino , Neoplasias Renais/patologia , Neoplasias Renais/complicações , Nefrectomia , Rim Policístico Autossômico Dominante/complicações , Rim Policístico Autossômico Dominante/patologia , Estudos Retrospectivos , Tumor de Wilms/patologia , Tumor de Wilms/complicaçõesRESUMO
OBJECTIVE: To investigate the correlation between programmed death ligand-1 (PD-L1) expression and tumor-infiltrating lymphocytes (TILs) and evaluate the prognostic value of PD-L1 and TILs in Chinese triple-negative breast cancer (TNBC) patients with different molecular subtype METHODS: This retrospective study was conducted at 2020. Specifically, the pre-chemotherapy clinical data and non-stained tissue blocks of 465 TNBC patients visited the Fudan University Shanghai Cancer Center (FUSCC) between 2008 and 2014 were collected, with their blocks sliced and stained using PD-L1(SP142), and the outcome of subsequent chemotherapy obtained in 2020. The relapse-free survival (RFS) of the study population was calculated. The baseline PD-L1 expression status correlations with TILs and molecular subtypes were assessed using Spearman's rank correlation analysis and the Kruskal-Wallis test. Kaplan-Meier survival analyses were undertaken to evaluate the prognosis value of TILs and PD-L1 expression. RESULTS: PD-L1 expression status on IC was moderately and positively correlated with stromal tumor-infiltrating lymphocytes (sTILs) (rs = 0.502, P <0.001) and iTILs (rs = 0.410, P < 0.001), respectively. PD-L1 expression status and TILs showed significant differences among molecular subtypes (P < 0.001), with the highest proportion of PD-L1+ and high TILs patients observed in the immunomodulatory (IM) subtype. TILs were significantly associated with RFS. Moreover, sTILs could act as an independent predictor of RFS (RR 0.953, 95â¯% CI 0.920 â¼ 0.987, P = 0.007), while PD-L1 expression status did not show the same prognostic significance. CONCLUSIONS: The incorporation of pre-treatment TILs and PD-L1 expression status as valuable tools for optimizing patient selection for immunotherapy and managing the risks associated with chemotherapy in Chinese TNBC patients. DATA AVAILABILITY: The data sets generated and analyzed during the current study are available from the corresponding author.
Assuntos
Antígeno B7-H1 , Biomarcadores Tumorais , Linfócitos do Interstício Tumoral , Neoplasias de Mama Triplo Negativas , Humanos , Linfócitos do Interstício Tumoral/imunologia , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/mortalidade , Antígeno B7-H1/metabolismo , Antígeno B7-H1/análise , Feminino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Adulto , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Idoso , China , População do Leste AsiáticoRESUMO
Avian influenza virus (AIV) subtype H9N2 has significantly threatened the poultry business in recent years by having become the predominant subtype in flocks of chickens, ducks, and pigeons. In addition, the public health aspects of H9N2 AIV pose a significant threat to humans. Early and rapid diagnosis of H9N2 AIV is therefore of great importance. In this study, a new method for the detection of H9N2 AIV based on fluorescence intensity was successfully established using CRISPR/Cas13a technology. The Cas13a protein was first expressed in a prokaryotic system and purified using nickel ion affinity chromatography, resulting in a high-purity Cas13a protein. The best RPA (recombinase polymerase amplification) primer pairs and crRNA were designed and screened, successfully constructing the detection of H9N2 AIV based on CRISPR/Cas13a technology. Optimal concentration of Cas13a and crRNA was determined to optimize the constructed assay. The sensitivity of the optimized detection system is excellent, with a minimum detection limit of 10° copies/µL and didn't react with other avian susceptible viruses, with excellent specificity. The detection method provides the basis for the field detection of the H9N2 AIV.
Assuntos
Sistemas CRISPR-Cas , Galinhas , Edição de Genes , Vírus da Influenza A Subtipo H9N2 , Influenza Aviária , Doenças das Aves Domésticas , Vírus da Influenza A Subtipo H9N2/genética , Vírus da Influenza A Subtipo H9N2/isolamento & purificação , Influenza Aviária/virologia , Influenza Aviária/diagnóstico , Animais , Edição de Genes/métodos , Edição de Genes/veterinária , Doenças das Aves Domésticas/virologia , Doenças das Aves Domésticas/diagnóstico , PatosRESUMO
HER2-positive breast cancer is an aggressive subtype that accounts for 15-20% of all breast cancers. Recent studies have suggested that HER2-positive breast cancer is a group of heterogeneous diseases with different sensitivities to standard treatment regimens. Revealing the molecular heterogeneity of HER2-positive breast cancer could potentially enable more precise treatment strategies. Here, we performed multiomics profiling on a HER2-positive breast cancer cohort and identified four transcriptome-based subtypes. The classical HER2 (HER2-CLA) subtype comprised 28.3% of the samples and displayed high ERBB2 activation and significant benefit from anti-HER2 therapy. The immunomodulatory (HER2-IM) subtype (20%) featured an immune-activated microenvironment, potentially suitable for de-escalated treatment and immunotherapy. The luminal-like (HER2-LUM) subtype (30.6%) possessed similar molecular features of hormone receptor-positive HER2-negative breast cancer, suggesting endocrine therapy and CDK4/6 inhibitors as a potential therapeutic strategy. Lastly, the basal/mesenchymal-like (HER2-BM) subtype (21.1%), had a poor response to current anti-HER2 dual-targeted therapies and could potentially benefit from tyrosine kinase inhibitors. The molecular characteristics and clinical features of the subtypes were further explored across multiple cohorts, and the feasibility of the proposed treatment strategies was validated in patient-derived organoid and patient-derived tumor fragment models. This study elucidates the molecular heterogeneity of HER2-positive breast cancer and paves the way for a more tailored treatment.
RESUMO
BACKGROUND: Whole-slide imaging (WSI) is a promising tool in pathology. However, the use of WSI in cytopathology has lagged behind that in histology. We aimed to evaluate the utility of WSI for the intraoperative touch imprint cytological diagnosis of axillary sentinel lymph nodes (SLNs) in breast cancer patients. METHODS: Glass slides from touch imprint cytology of 480 axillary SLNs were scanned using two different WSI scanners. The intra- and interobserver concordance, accuracy, possible reasons for misdiagnosis, scanning time, and review time for three cytopathologists were compared between WSI and light microscopy (LM). RESULTS: A total of 4320 diagnoses were obtained. There was substantial to strong intraobserver concordance when comparing reads among paired LM slides and WSI digital slides (κ coefficient ranged from 0.63 to 0.88, and concordance rates ranged from 94.58% to 98.33%). Substantial to strong interobserver agreement was also observed among the three cytopathologists (κ coefficient ranged from 0.67 to 0.85, and concordance rates ranged from 95.42% to 97.92%). The accuracy of LM was slightly higher (average of 98.06%) than that of WSI (averages of 96.81% and 97.78%). The majority of misdiagnoses were false negative diagnoses due to the following top three causes: few cancer cells, confusing cancer cells with histiocytes, and confusing cancer cells with lymphocytes. CONCLUSIONS: This study is the first to address the feasibility of WSI in touch imprint cytology. The use of WSI for intraoperative touch imprint cytological diagnosis of SLNs is a practical option when experienced staff are not available on-site.
RESUMO
In maintaining organismal homeostasis, gut immunity plays a crucial role. The coordination between the microbiota and the immune system through bidirectional interactions regulates the impact of microorganisms on the host. Our research focused on understanding the relationships between substantial changes in jejunal intestinal flora and metabolites and intestinal immunity during porcine epidemic diarrhea virus (PEDV) infection in piglets. We discovered that Lactobacillus rhamnosus GG (LGG) could effectively prevent PEDV infection in piglets. Further investigation revealed that LGG metabolites interact with type 3 innate lymphoid cells (ILC3s) in the jejunum of piglets through the aryl hydrocarbon receptor (AhR). This interaction promotes the activation of ILC3s and the production of interleukin-22 (IL-22). Subsequently, IL-22 facilitates the proliferation of IPEC-J2 cells and activates the STAT3 signaling pathway, thereby preventing PEDV infection. Moreover, the AhR receptor influences various cell types within organoids, including intestinal stem cells (ISCs), Paneth cells, and enterocytes, to promote their growth and development, suggesting that AhR has a broad impact on intestinal health. In conclusion, our study demonstrated the ability of LGG to modulate intestinal immunity and effectively prevent PEDV infection in piglets. These findings highlight the potential application of LGG as a preventive measure against viral infections in livestock.IMPORTANCEWe observed high expression of the AhR receptor on pig and human ILC3s, although its expression was negligible in mouse ILC3s. ILC3s are closely related to the gut microbiota, particularly the secretion of IL-22 stimulated by microbial signals, which plays a crucial regulatory role in intestinal immunity. In our study, we found that metabolites produced by beneficial gut bacteria interact with ILC3s through AhR, thereby maintaining intestinal immune homeostasis in pigs. Moreover, LGG feeding can enhance the activation of ILC3s and promote IL-22 secretion in the intestines of piglets, ultimately preventing PEDV infection.
Assuntos
Infecções por Coronavirus , Imunidade Inata , Interleucina 22 , Interleucinas , Linfócitos , Vírus da Diarreia Epidêmica Suína , Receptores de Hidrocarboneto Arílico , Animais , Receptores de Hidrocarboneto Arílico/metabolismo , Suínos , Interleucinas/metabolismo , Vírus da Diarreia Epidêmica Suína/imunologia , Linfócitos/imunologia , Linfócitos/metabolismo , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/veterinária , Infecções por Coronavirus/virologia , Infecções por Coronavirus/metabolismo , Microbioma Gastrointestinal/imunologia , Doenças dos Suínos/imunologia , Doenças dos Suínos/virologia , Doenças dos Suínos/prevenção & controle , Doenças dos Suínos/microbiologia , Jejuno/imunologia , Jejuno/metabolismo , Transdução de Sinais , Ligantes , Intestinos/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismoRESUMO
The impacts of straw removal on rice Cd absorption, behaviour of Cd and microbial community in rhizosphere soil were investigated in paddy fields over two consecutive seasons. The results of the experiments in two fields revealed that straw removal promoted the transformation of soil Cd from acid-extractable and oxidisable fraction to residual fraction and reduced soil DTPA-Cd content with the reduction in DOC and Cd ions in soil porewater, thereby decreasing Cd content in rice. Specifically, the Cd content in brown rice was below 0.2 mg·kg-1 when all rice straw and roots were removed in the slightly Cd-contaminated soils. The α-diversity of soil microbial communities was less influenced by continuous straw removal, ß-diversity was altered and the relative abundances of Anaeromyxobacter, Methylocystis and Mycobacterium microbes were increased. Redundancy analysis and network analysis exhibited that soil pH predominantly influenced the microbial community. Path analysis revealed that the Cd content in brown rice could be directly influenced by the soil Total-Cd and DTPA-Cd, as well as soil pH and OM. Straw removal, including roots removal, is an economical and effective technique to reduce Cd accumulation in rice plants.
Assuntos
Cádmio , Oryza , Microbiologia do Solo , Poluentes do Solo , Oryza/metabolismo , Cádmio/metabolismo , Cádmio/análise , Poluentes do Solo/metabolismo , Solo/química , Raízes de Plantas/metabolismo , Raízes de Plantas/microbiologia , Rizosfera , Agricultura , Bactérias/metabolismo , Concentração de Íons de Hidrogênio , MicrobiotaRESUMO
BACKGROUND: Previous observational studies have shown that the prevalence of gastroesophageal reflux disease (GERD) and Barrett's esophagus (BE) is associated with socioeconomic status. However, due to the methodological limitations of traditional observational studies, it is challenging to definitively establish causality. AIM: To explore the causal relationship between the prevalence of these conditions and socioeconomic status using Mendelian randomization (MR). METHODS: We initially screened single nucleotide polymorphisms (SNPs) to serve as proxies for eight socioeconomic status phenotypes for univariate MR analysis. The inverse variance weighted (IVW) method was used as the primary analytical method to estimate the causal relationship between the eight socioeconomic status phenotypes and the risk of GERD and BE. We then collected combinations of SNPs as composite proxies for the eight socioeconomic phenotypes to perform multivariate MR (MVMR) analyses based on the IVW MVMR model. Furthermore, a two-step MR mediation analysis was used to examine the potential mediation of the associations by body mass index, major depressive disorder (MDD), smoking, alcohol consumption, and sleep duration. RESULTS: The study identified three socioeconomic statuses that had a significant impact on GERD. These included household income [odds ratio (OR): 0.46; 95% confidence interval (95%CI): 0.31-0.70], education attainment (OR: 0.23; 95%CI: 0.18-0.29), and the Townsend Deprivation Index at recruitment (OR: 1.57; 95%CI: 1.04-2.37). These factors were found to independently and predominantly influence the genetic causal effect of GERD. Furthermore, the mediating effect of educational attainment on GERD was found to be mediated by MDD (proportion mediated: 10.83%). Similarly, the effect of educational attainment on BE was mediated by MDD (proportion mediated: 10.58%) and the number of cigarettes smoked per day (proportion mediated: 3.50%). Additionally, the mediating effect of household income on GERD was observed to be mediated by sleep duration (proportion mediated: 9.75%). CONCLUSION: This MR study shed light on the link between socioeconomic status and GERD or BE, providing insights for the prevention of esophageal cancer and precancerous lesions.
RESUMO
OBJECTIVE: To identify recurrent venous thromboembolism (VTE) after discontinuation of anticoagulation in patients with isolated distal deep vein thrombosis based on its anatomic localization (axial or muscular veins). METHODS: Data were sourced from PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov databases in the time period up to October 2023. The study followed PRISMA guidelines using a registered protocol (CRD42023443029). Studies reporting recurrent VTE in patients with axial or muscular DVT were included in the analysis. RESULTS: Five studies with a total of 1,403 participants were evaluated. The results showed a pooled odds ratio of 1.12 (95% confidence interval 0.77-1.63) between axial and muscular DVT. Heterogeneity was low (I2 = 0%, p = 0.91) and there was no significant difference in the rate of recurrent VTE between axial and muscular DVT in each subgroup. CONCLUSIONS: Muscular and axial DVT showed comparable recurrent VTE rates after anticoagulation. However, uncertainties regarding the possibility of recurrence affecting the popliteal vein or resulting in pulmonary embolism following muscular DVT anticoagulation persisted. Randomized trials in patients with isolated distal DVT are still needed to clarify its prognosis for different anatomical thrombus locations.
RESUMO
Phthalate esters (PAEs), widely recognized as synthetic organic compounds with extensive production and utilization, are known to disrupt physiological processes in both animals and humans, even at low environmental concentrations. This study investigated the occurrence, distribution, and potential ecological risk of five representative PAEs (DMP, Dimethyl phthalate; DEP, Diethyl phthalate; DBP, Dibutyl phthalate; DiBP, Diisobutyl phthalate; DEHP, Bis(2-ethylhexyl) phthalate) in a typical lake (Chaohu Lake, China). It was found that PAEs were detected in both the aqueous (1.09-6.402 µg/L) and solid phases (0.827-6.602 µg/g) of Chaohu Lake. Notably, DiBP and DBP were the predominant PAEs in the water, and DiBP and DEHP were the most prevalent in the sediments. The concentrations of PAEs exhibited significant seasonal variations in the aqueous phases, with total PAEs in summer being nearly twice those in winter. Toxicity assessments revealed that DEHP, DBP, and DiBP posed high risks to the survival of three indicator organisms (algae, Daphnia, and fish) in the aqueous phase. In the solid phase, the exceeding rate of DiBP was as high as 92.9%. On the other hand, DBP and DEHP generally presenting moderate risk, although some sites were identified as high-risk. This study's analysis of PAEs concentrations in Chaohu Lake reveals a discernible increasing trend when compared with historical data. These findings underscore the urgent need for interventions to mitigate the ecological threats posed by PAEs in Chaohu Lake.