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Colorectal cancer (CRC) is a major global health concern, and the development of effective treatment strategies is crucial. Enzyme prodrug therapy (EPT) shows promise in combating tumors but faces challenges in achieving sustained expression of therapeutic enzymes and optimal biological distribution. To address these issues, a fungi-triggered in situ chemotherapeutics generator (named as SC@CS@5-FC) was constructed via oral delivery of a prodrug (5-fluorocytosine, 5-FC) for the treatment of orthotopic colorectal tumor. When SC@CS@5-FC targets the tumor through tropism by Saccharomyces cerevisiae (SC), the chemotherapeutic generator could be degraded under abundant hyaluronidase (HAase) in the tumor microenvironment by an enzyme-responsive gate to release prodrug (5-FC). And nontoxic 5-FC was catalyzed to toxic chemotherapy drug 5-fluorouracil (5-FU) by cytosine deaminase (CD) of SC. Meanwhile, SC and zinc-coordinated chitosan nanoparticles could be used as immune adjuvants to activate antigen-presenting cells and further enhance the therapeutic effect. Our results demonstrated that SC@CS@5-FC could effectively inhibit tumor growth and prolong mouse survival in an orthotopic colorectal cancer model. This work utilizes living SC as a dynamotor and positioning system for the chemotherapeutic generator SC@CS@5-FC, providing a strategy for oral enzyme prodrug therapy for the treatment of orthotopic colorectal.
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Thymic epithelial cells (TECs) play an essential role in promoting the development and repertoire selection of T cells. Cortical TECs (cTECs) in the thymic cortex induce early T cell development and positive selection of cortical thymocytes. In contrast, medullary TECs (mTECs) in the thymic medulla attract positively selected thymocytes from the cortex and establish self-tolerance in T cells. A variety of molecules, including DLL4 and beta5t expressed in cTECs, as well as Aire and CCL21 expressed in mTECs, contribute to thymus function supporting T cell development and selection. Flow cytometric analysis of functionally relevant molecules in cTECs and mTECs is useful to improve our understanding of the biology of TECs, even though current methods for the preparation of single-cell suspensions of TECs can retrieve only a small fraction of TECs (approximately 1% for cTECs and approximately 10% for mTECs) from young adult mouse thymus. Because many of these functionally relevant molecules in TECs are localized within the cells, we describe our protocols for the preparation of single-cell suspension of mouse TECs and the staining of intracellular molecules for flow cytometric analysis.
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Células Epiteliales , Citometría de Flujo , Timo , Animales , Ratones , Células Epiteliales/citología , Células Epiteliales/metabolismo , Células Epiteliales/química , Timo/citología , Timo/metabolismo , Citometría de Flujo/métodosRESUMEN
A growing number of studies have demonstrated that repeated exposure to sevoflurane during development results in persistent social abnormalities and cognitive impairment. Davunetide, an active fragment of the activity-dependent neuroprotective protein (ADNP), has been implicated in social and cognitive protection. However, the potential of davunetide to attenuate social deficits following sevoflurane exposure and the underlying developmental mechanisms remain poorly understood. In this study, ribosome and proteome profiles were analyzed to investigate the molecular basis of sevoflurane-induced social deficits in neonatal mice. The neuropathological basis was also explored using Golgi staining, morphological analysis, western blotting, electrophysiological analysis, and behavioral analysis. Results indicated that ADNP was significantly down-regulated following developmental exposure to sevoflurane. In adulthood, anterior cingulate cortex (ACC) neurons exposed to sevoflurane exhibited a decrease in dendrite number, total dendrite length, and spine density. Furthermore, the expression levels of Homer, PSD95, synaptophysin, and vglut2 were significantly reduced in the sevoflurane group. Patch-clamp recordings indicated reductions in both the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs). Notably, davunetide significantly ameliorated the synaptic defects, social behavior deficits, and cognitive impairments induced by sevoflurane. Mechanistic analysis revealed that loss of ADNP led to dysregulation of Ca 2+ activity via the Wnt/ß-catenin signaling, resulting in decreased expression of synaptic proteins. Suppression of Wnt signaling was restored in the davunetide-treated group. Thus, ADNP was identified as a promising therapeutic target for the prevention and treatment of neurodevelopmental toxicity caused by general anesthetics. This study provides important insights into the mechanisms underlying social and cognitive disturbances caused by sevoflurane exposure in neonatal mice and elucidates the regulatory pathways involved.
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Disfunción Cognitiva , Proteínas del Tejido Nervioso , Proteoma , Ribosomas , Sevoflurano , Conducta Social , Animales , Masculino , Ratones , Anestésicos por Inhalación/efectos adversos , Anestésicos por Inhalación/toxicidad , Anestésicos por Inhalación/farmacología , Animales Recién Nacidos , Conducta Animal/efectos de los fármacos , Disfunción Cognitiva/inducido químicamente , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/metabolismo , Ribosomas/efectos de los fármacos , Ribosomas/metabolismoRESUMEN
This study investigated the effect of Erchen Decoction(ECD) on the prevention of non-alcoholic steatohepatitis(NASH) in mice and explored its possible mechanism, so as to provide scientific data for the clinical application of ECD in the prevention of NASH. C57BL/6 male mice were randomly divided into normal group(methionine and choline supplement, MCS), model group(methionine and choline deficient, MCD), low-dose ECD group(ECD_L, 6 g·kg~(-1)), medium-dose ECD group(ECD_M, 12 g·kg~(-1)), and high-dose ECD group(ECD_H, 24 g·kg~(-1)), with eight mice in each group. The MCS group was fed with an MCS diet, and the other groups were fed with an MCD diet. The mice in each group were given corresponding diets, but the drug intervention group was given low-, medium-, and high-dose ECD(10 mL·kg~(-1)·d~(-1)) by intragastric administration for six weeks on the basis of MCD diet feeding, and the mice could eat and drink freely during the whole experiment. At the end of the experiment, mice were fasted overnight(12 h) and were anesthetized with 20% urethane. Thereafter, the blood and liver tissue were collected. The serum was used to detect the levels of alanine aminotransferase(ALT), aspartate aminotransaminase(AST), interleukin-1ß(IL-1ß), interleukin-6(IL-6), interleukin-10(IL-10), and tumor necrosis factor-α(TNF-α). Liver tissue was processed by hematoxylin-eosin(HE) staining and used for hepatic histological analysis and detection of the expression levels of genes and proteins related to nuclear factor erythroid 2-related factor 2/glutathione peroxidase 4(Nrf2/GPX4) pathway by real-time quantitative reverse transcriptase-polymerase chain reaction(RT-qPCR) and Western blot analysis, respectively. The results showed that compared with the MCS group, the MCD group showed higher serum ALT and AST levels; the HE staining exhibited fat vacuoles and obvious inflammatory cell infiltration in liver tissue; serum IL-1ß, IL-6, and TNF-α levels were significantly increased, and the serum IL-10 level was significantly decreased. The mRNA expressions of fatty acid synthase(FASN), monocyte chemoattractant protein-1(MCP-1), and IL-1ß in liver tissue were significantly up-regulated, while those of GPX4, Nrf2, and NAD(P)H:quinine oxidoreductase(NQO1) were significantly down-regulated. Compared with the MCD group, the serum ALT and AST levels of ECD_M and ECD_H groups were significantly decreased, and the AST level in the ECD_L group was significantly decreased. The number of fat vacuoles and the degree of inflammatory cell infiltration in liver tissue were improved; serum IL-1ß, IL-6, and TNF-α levels were significantly decreased, but the serum IL-10 level was significantly increased only in the ECD_H group. The mRNA expressions of FASN, MCP-1, and IL-1ß in liver tissue were significantly down-regulated, and those of GPX4 and NQO1 were significantly up-regulated. The mRNA expressions of Nrf2 in ECD_M and ECD_H groups were significantly up-regulated. Western blot results showed that compared with the MCD group, the protein expression levels of Nrf2 and GPX4 in each group were significantly increased after ECD administration, and the protein expression level of FASN was significantly decreased; the protein expression of NQO1 was increased in ECD_M and ECD_H groups. In summary, ECD can reduce hepatic lipid accumulation, oxidative stress, liver inflammation, and liver injury in NASH mice, which may be related to the activation of the Nrf2/GPX4 pathway.
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Enfermedad del Hígado Graso no Alcohólico , Ratones , Masculino , Animales , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/genética , Metionina/metabolismo , Metionina/farmacología , Interleucina-10/genética , Colina/metabolismo , Colina/farmacología , Colina/uso terapéutico , Factor de Necrosis Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Ratones Endogámicos C57BL , Hígado , Racemetionina/metabolismo , Racemetionina/farmacología , Dieta , ARN Mensajero/metabolismoAsunto(s)
Nódulo Tiroideo , Humanos , Estudios de Casos y Controles , Suero , Índice de Masa CorporalRESUMEN
Plants must adapt to the complex effects of several stressors brought on by global warming, which may result in interaction and superposition effects between diverse stressors. Few reports are available on how drought stress affects Xanthomonas albilineans (Xa) infection in sugarcane (Saccharum spp. hybrids). Drought and leaf scald resistance were identified on 16 sugarcane cultivars using Xa inoculation and soil drought treatments, respectively. Subsequently, four cultivars contrasting to drought and leaf scald resistance were used to explore the mechanisms of drought affecting Xa-sugarcane interaction. Drought stress significantly increased the occurrence of leaf scald and Xa populations in susceptible cultivars but had no obvious effect on resistant cultivars. The ROS bursting and scavenging system was significantly activated in sugarcane in the process of Xa infection, particularly in the resistant cultivars. Compared with Xa infection alone, defense response via the ROS generating and scavenging system was obviously weakened in sugarcane (especially in susceptible cultivars) under Xa infection plus drought stress. Collectively, ROS might play a crucial role involving sugarcane defense against combined effects of Xa infection and drought stress.
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Pulmonary fibrosis is a lung disorder affecting the lungs that involves the overexpressed extracellular matrix, scarring and stiffening of tissue. The repair of lung tissue after injury relies heavily on Type II alveolar epithelial cells (AEII), and repeated damage to these cells is a crucial factor in the development of pulmonary fibrosis. Studies have demonstrated that chronic exposure to PM2.5, a form of air pollution, leads to an increase in the incidence and severity of pulmonary fibrosis by stimulation of epithelial-mesenchymal transition (EMT) in lung epithelial cells. Pyrroloquinoline quinone (PQQ) is a bioactive compound found naturally that exhibits potent anti-inflammatory and anti-oxidative properties. The mechanism by which PQQ prevents pulmonary fibrosis caused by exposure to PM2.5 through EMT has not been thoroughly discussed until now. In the current study, we discovered that PQQ successfully prevented PM2.5-induced pulmonary fibrosis by targeting EMT. The results indicated that PQQ was able to inhibit the expression of type I collagen, a well-known fibrosis marker, in AEII cells subjected to long-term PM2.5 exposure. We also found the alterations of cellular structure and EMT marker expression in AEII cells with PM2.5 incubation, which were reduced by PQQ treatment. Furthermore, prolonged exposure to PM2.5 considerably reduced cell migratory ability, but PQQ treatment helped in reducing it. In vivo animal experiments indicated that PQQ could reduce EMT markers and enhance pulmonary function. Overall, these results imply that PQQ might be useful in clinical settings to prevent pulmonary fibrosis.
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Fibrosis Pulmonar , Animales , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/tratamiento farmacológico , Cofactor PQQ/farmacología , Transición Epitelial-Mesenquimal , Células Epiteliales Alveolares , Material Particulado/toxicidadRESUMEN
Pulmonary fibrosis is a lung disorder characterized by the accumulation of abnormal extracellular matrix, scar tissue formation, and tissue stiffness. Type II alveolar epithelial cells (AEII) play a critical role in repairing lung tissue after injury, and repeated injury to these cells is a key factor in the development of pulmonary fibrosis. Chronic exposure to PM2.5, a type of air pollution, has been shown to increase the incidence and severity of pulmonary fibrosis by enhancing the activation of EMT in lung epithelial cells. Melatonin, a hormone with antioxidant properties, has been shown to prevent EMT and reduce fibrosis in previous studies. However, the mechanism through which melatonin targets EMT to prevent pulmonary fibrosis caused by PM2.5 exposure has not been extensively discussed before. In this current study, we found that melatonin effectively prevented pulmonary fibrosis caused by prolonged exposure to PM2.5 by targeting EMT. The study demonstrated changes in cellular morphology and expression of EMT markers. Furthermore, the cell migratory potential induced by prolonged exposure to PM2.5 was greatly reduced by melatonin treatment. Finally, in vivo animal studies showed reduced EMT markers and improved pulmonary function. These findings suggest that melatonin has potential clinical use for the prevention of pulmonary fibrosis.
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Transición Epitelial-Mesenquimal , Melatonina , Material Particulado , Fibrosis Pulmonar , Melatonina/farmacología , Melatonina/uso terapéutico , Transición Epitelial-Mesenquimal/efectos de los fármacos , Animales , Fibrosis Pulmonar/prevención & control , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/patología , Material Particulado/toxicidad , Masculino , Ratones , Ratones Endogámicos C57BL , Movimiento Celular/efectos de los fármacos , Humanos , Células Epiteliales Alveolares/efectos de los fármacos , Células Epiteliales Alveolares/patología , Células Epiteliales Alveolares/metabolismo , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/metabolismo , Antioxidantes/farmacología , Antioxidantes/uso terapéuticoRESUMEN
In recent years, various types of immunotherapy, particularly the use of immune checkpoint inhibitors targeting programmed cell death 1 or programmed death ligand 1 (PD-L1), have revolutionized the management and prognosis of non-small cell lung cancer. PD-L1 is frequently used as a biomarker for predicting the likely benefit of immunotherapy for patients. However, some patients receiving immunotherapy have high response rates despite having low levels of PD-L1. Therefore, the identification of this group of patients is extremely important to improve prognosis. The tumor microenvironment contains tumor, stromal, and infiltrating immune cells with its composition differing significantly within tumors, between tumors, and between individuals. The omics approach aims to provide a comprehensive assessment of each patient through high-throughput extracted features, promising a more comprehensive characterization of this complex ecosystem. However, features identified by high-throughput methods are complex and present analytical challenges to clinicians and data scientists. It is thus feasible that artificial intelligence could assist in the identification of features that are beyond human discernment as well as in the performance of repetitive tasks. In this paper, we review the prediction of immunotherapy efficacy by different biomarkers (genomic, transcriptomic, proteomic, microbiomic, and radiomic), together with the use of artificial intelligence and the challenges and future directions of these fields.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Antígeno B7-H1/metabolismo , Inteligencia Artificial , Multiómica , Ecosistema , Proteómica , Biomarcadores de Tumor/metabolismo , Inmunoterapia/métodos , Microambiente TumoralRESUMEN
In digenic inheritance, pathogenic variants in two genes must be inherited together to cause disease. Only very few examples of digenic inheritance have been described in the neuromuscular disease field. Here we show that predicted deleterious variants in SRPK3, encoding the X-linked serine/argenine protein kinase 3, lead to a progressive early onset skeletal muscle myopathy only when in combination with heterozygous variants in the TTN gene. The co-occurrence of predicted deleterious SRPK3/TTN variants was not seen among 76,702 healthy male individuals, and statistical modeling strongly supported digenic inheritance as the best-fitting model. Furthermore, double-mutant zebrafish (srpk3-/-; ttn.1+/-) replicated the myopathic phenotype and showed myofibrillar disorganization. Transcriptome data suggest that the interaction of srpk3 and ttn.1 in zebrafish occurs at a post-transcriptional level. We propose that digenic inheritance of deleterious changes impacting both the protein kinase SRPK3 and the giant muscle protein titin causes a skeletal myopathy and might serve as a model for other genetic diseases.
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Enfermedades Musculares , Pez Cebra , Animales , Humanos , Masculino , Conectina/genética , Conectina/metabolismo , Músculo Esquelético , Enfermedades Musculares/genética , Enfermedades Musculares/metabolismo , Enfermedades Musculares/patología , Mutación , Pez Cebra/genéticaRESUMEN
Sugarcane (Saccharum spp.) is an important sugar and biofuel crop in the world. It is frequently subjected to drought stress, thus causing considerable economic losses. Transgenic technology is an effective breeding approach to improve sugarcane tolerance to drought using drought-inducible promoter(s) to activate drought-resistance gene(s). In this study, six different promoters were cloned from sugarcane bacilliform virus (SCBV) genotypes exhibiting high genetic diversity. In ß-glucuronidase (GUS) assays, expression of one of these promoters (PSCBV-YZ2060) is similar to the one driven by the CaMV 35S promoter and >90% higher compared to the other cloned promoters and Ubi1. Three SCBV promoters (PSCBV-YZ2060, PSCBV-TX, and PSCBV-CHN2) function as drought-induced promoters in transgenic Arabidopsis plants. In Arabidopsis, GUS activity driven by promoter PSCBV-YZ2060 is also upregulated by abscisic acid (ABA) and is 2.2-5.5-fold higher when compared to the same activity of two plant native promoters (PScRD29A from sugarcane and PAtRD29A from Arabidopsis). Mutation analysis revealed that a putative promoter region 1 (PPR1) and two ABA response elements (ABREs) are required in promoter PSCBV-YZ2060 to confer drought stress response and ABA induction. Yeast one-hybrid and electrophoretic mobility shift assays uncovered that transcription factors ScbZIP72 from sugarcane and AREB1 from Arabidopsis bind with two ABREs of promoter PSCBV-YZ2060. After ABA treatment or drought stress, the expression levels of endogenous ScbZIP72 and heterologous GUS are significantly increased in PSCBV-YZ2060:GUS transgenic sugarcane plants. Consequently, promoter PSCBV-YZ2060 is a possible alternative promoter for genetic engineering of drought-resistant transgenic crops such as sugarcane.
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Arabidopsis , Badnavirus , Arabidopsis/genética , Sequías , Fitomejoramiento , Regiones Promotoras Genéticas , Plantas Modificadas Genéticamente/genéticaRESUMEN
Thymus medulla epithelium establishes immune self-tolerance and comprises diverse cellular subsets. Functionally relevant medullary thymic epithelial cells (mTECs) include a self-antigen-displaying subset that exhibits genome-wide promiscuous gene expression promoted by the nuclear protein Aire and that resembles a mosaic of extrathymic cells including mucosal tuft cells. An additional mTEC subset produces the chemokine CCL21, thereby attracting positively selected thymocytes from the cortex to the medulla. Both self-antigen-displaying and thymocyte-attracting mTEC subsets are essential for self-tolerance. Here, we identify a developmental pathway by which mTECs gain their diversity in functionally distinct subsets. We show that CCL21-expressing mTECs arise early during thymus ontogeny in mice. Fate-mapping analysis reveals that self-antigen-displaying mTECs, including Aire-expressing mTECs and thymic tuft cells, are derived from CCL21-expressing cells. The differentiation capability of CCL21-expressing embryonic mTECs is verified in reaggregate thymus experiments. These results indicate that CCL21-expressing embryonic mTECs carry a developmental potential to give rise to self-antigen-displaying mTECs, revealing that the sequential conversion of thymocyte-attracting subset into self-antigen-displaying subset serves to assemble functional diversity in the thymus medulla epithelium.
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Timocitos , Factores de Transcripción , Ratones , Animales , Timocitos/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Ratones Endogámicos C57BL , Timo/metabolismo , Diferenciación Celular , Células Epiteliales/metabolismo , Epitelio/metabolismoRESUMEN
Large-scale imaging of neuronal activities is crucial for understanding brain functions. However, it is challenging to analyze large-scale imaging data in real time, preventing closed-loop investigation of neural circuitry. Here we develop a real-time analysis system with a field programmable gate array-graphics processing unit design for an up to 500-megabyte-per-second image stream. Adapted to whole-brain imaging of awake larval zebrafish, the system timely extracts activity from up to 100,000 neurons and enables closed-loop perturbations of neural dynamics.
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Encéfalo , Neuronas , Pez Cebra , Animales , Neuronas/fisiología , Encéfalo/fisiología , Encéfalo/diagnóstico por imagen , Procesamiento de Imagen Asistido por Computador/métodos , Larva , Neuroimagen/métodos , Sistemas de ComputaciónRESUMEN
BACKGROUND: The existence of pancreatic cancer stem cells (PCSCs) results in limited survival benefits from current treatment options. There is a scarcity of effective agents for treating pancreatic cancer patients. Dehydroevodiamine (DeHE), a quinazoline alkaloid isolated from the traditional Chinese herb Evodiae fructus, exhibited potent inhibition of pancreatic ductal adenocarcinoma (PDAC) cell proliferation and tumor growth both in vitro and in vivo. METHODS: The cytotoxic effect of DeHE on PDAC cells was assessed using CCK-8 and colony formation assays. The antitumor efficacy of DeHE were appraised in human PANC-1 xenograft mouse model. Sphere formation assay and flow cytometry were employed to quantify the tumor stemness. RNA-Seq analysis, drug affinity responsive target stability assay (DARTS), and RNA interference transfection were conducted to elucidate potential signaling pathways. Western blotting and immunohistochemistry were utilized to assess protein expression levels. RESULTS: DeHE effectively inhibited PDAC cell proliferation and tumor growth in vitro and in vivo, and exhibited a better safety profile compared to the clinical drug gemcitabine (GEM). DeHE inhibited PCSCs, as evidenced by its suppression of self-renewal capabilities of PCSCs, reduced the proportion of ALDH+ cells and downregulated stemness-associated proteins (Nanog, Sox-2, and Oct-4) both in vitro and in vivo. Furthermore, there is potential involvement of DDIT3 and its downstream DDIT3/TRIB3/AKT/mTOR pathway in the suppression of stemness characteristics within DeHE-treated PDAC cells. Additionally, results from the DARTS assay indicated that DeHE interacts with DDIT3, safeguarding it against degradation mediated by pronase. Notably, the inhibitory capabilities of DeHE on PDAC cell proliferation and tumor stemness were partially restored by siDDIT3 or the AKT activator SC-79. CONCLUSION: In summary, our study has identified DeHE, a novel antitumor natural product, as an activator of DDIT3 with the ability to suppress the AKT/mTOR pathway. This pathway is intricately linked to tumor cell proliferation and stemness characteristics in PDAC. These findings suggest that DeHE holds potential as a promising candidate for the development of innovative anticancer therapeutics.
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Proliferación Celular , Células Madre Neoplásicas , Neoplasias Pancreáticas , Animales , Humanos , Ratones , Antineoplásicos Fitogénicos/farmacología , Carcinoma Ductal Pancreático/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Evodia/química , Gemcitabina , Ratones Endogámicos BALB C , Ratones Desnudos , Células Madre Neoplásicas/efectos de los fármacos , Neoplasias Pancreáticas/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Quinazolinas/farmacología , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Factor de Transcripción CHOP/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Immune checkpoint inhibitors (ICIs) can lead to life-threatening pneumonitis, and pre-existing interstitial lung abnormalities (ILAs) are a risk factor for checkpoint inhibitor pneumonitis (CIP). However, the subjective assessment of ILA and the lack of standardized methods restrict its clinical utility as a predictive factor. This study aims to identify non-small cell lung cancer (NSCLC) patients at high risk of CIP using quantitative imaging. METHODS: This cohort study involved 206 cases in the training set and 111 cases in the validation set. It included locally advanced or metastatic NSCLC patients who underwent ICI therapy. A deep learning algorithm labeled the interstitial lesions and computed their volume. Two predictive models were developed to predict the probability of grade ≥ 2 CIP or severe CIP (grade ≥ 3). Cox proportional hazard models were employed to analyze predictors of progression-free survival (PFS). RESULTS: In a training cohort of 206 patients, 21.4% experienced CIP. Two models were developed to predict the probability of CIP based on different predictors. Model 1 utilized age, histology, and preexisting ground glass opacity (GGO) percentage of the whole lung to predict grade ≥ 2 CIP, while Model 2 used histology and GGO percentage in the right lower lung to predict grade ≥ 3 CIP. These models were validated, and their accuracy was assessed. In another exploratory analysis, the presence of GGOs involving more than one lobe on pretreatment CT scans was identified as a risk factor for progression-free survival. CONCLUSIONS: The assessment of GGO volume and distribution on pre-treatment CT scans could assist in monitoring and manage the risk of CIP in NSCLC patients receiving ICI therapy. CLINICAL RELEVANCE STATEMENT: This study's quantitative imaging and computational analysis can help identify NSCLC patients at high risk of CIP, allowing for better risk management and potentially improved outcomes in those receivingICI treatment.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Neumonía , Humanos , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/tratamiento farmacológico , Estudios de Cohortes , Pulmón/patología , Neumonía/patología , Tomografía Computarizada por Rayos X , Estudios RetrospectivosRESUMEN
Outer membrane vesicles (OMVs) are soluble mediators secreted by Gram-negative bacteria that are involved in communication. They can carry a variety of harmful molecules, which induce cytotoxic responses and inflammatory reactions in the absence of direct host cell-bacterium interactions. We previously reported the isolation of OMVs from avian pathogenic Escherichia coli (APEC) culture medium by ultracentrifugation, and characterized them as a substance capable of inducing the production of pro-inflammatory cytokines and causing tissue damage. However, the specific mechanisms by which APEC-secreted OMVs activate host cell death signaling and inflammation are poorly understood. Here, we show that OMVs are involved in the pathogenesis of APEC disease. In an APEC/chicken macrophage (HD11) coculture system, APEC significantly promoted HD11 cell death and inflammatory responses by secreting OMVs. Using western blotting analysis and specific pathway inhibitors, we demonstrated that the induction of HD11 death by APEC OMVs is associated with the activation of receptor interacting serine/threonine kinase 1 (RIPK1)-, receptor interacting serine/threonine kinase 3 (RIPK3)-, and mixed lineage kinase like pseudokinase (MLKL)-induced necroptosis. Notably, necroptosis inhibitor-1 (Nec-1), an RIPK1 inhibitor, reversed these effects. We also showed that APEC OMVs promote the activation of the NF-κB signaling pathway, leading to the phosphorylation of IκB-α and p65, the increased nuclear translocation of p65, and the significant upregulation of interleukin 1ß (IL-1ß) and IL-6 transcription. Importantly, APEC OMVs-induced IL-1ß and IL-6 mRNA expression and the activation of the NF-κB signaling pathway were similarly significantly inhibited by a RIPK1-specific inhibitor. Based on these findings, we have established that RIPK1 plays a dual role in HD11 cells necroptosis and the proinflammatory cytokine (IL-1ß and IL-6) expression induced by APEC OMVs. RIPK1 mediated the induction of necroptosis and the activation of the NF-κB in HD11 cells via APEC OMVs. The results of this study provide a basis for further investigation of the contribution of OMVs to the pathogenesis of APEC.
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Membrana Externa Bacteriana , Escherichia coli , FN-kappa B , Necroptosis , Proteína Serina-Treonina Quinasas de Interacción con Receptores , Animales , Pollos/metabolismo , Citocinas , Escherichia coli/metabolismo , Escherichia coli/patogenicidad , Inflamación/patología , Inflamación/veterinaria , Interleucina-6 , Macrófagos/metabolismo , Macrófagos/microbiología , FN-kappa B/metabolismo , Serina , Transducción de Señal , Membrana Externa Bacteriana/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismoRESUMEN
Patients with metastatic lung adenocarcinoma (MLA) and malignant pleural effusion (MPE) without driver gene mutations have a poor prognosis. None of the standard treatment strategies is recommended for such patients. We retrospectively analyzed the efficacy of the first-line treatment for this specific population: standard platinum-based doublet chemotherapy (CT), CT plus an immune checkpoint inhibitor (CT plus ICI), and CT plus bevacizumab (CT plus Bev). A total of 323 eligible patients were enrolled: CT alone (n = 166), CT plus Bev (n = 72), and CT plus ICI (n = 85). Treatment efficacy assessments were performed every two cycles according to the RECIST guidelines. The endpoints were overall survival (OS) and progression-free survival (PFS). Kaplan-Meier (KâM) curves and the log-rank test were used to compare OS and PFS. p < 0.05 was the threshold of significance (statistical software: SPSS). The median follow-up was 11.4 months (range, 2.1-49.6 months). PFS and OS in the CT plus ICI/CT plus Bev cohort were significantly longer than those in the CT group (PFS: 7.8/6.4/3.9 months, p < 0.0001; OS: 16.4/15.6/9.6 months, p < 0.0001, respectively). CT plus Bev had better PFS and OS than CT plus ICI/CT in PD-L1 < 1% patients (PFS: 8.4/5.0/3.8 months, p < 0.0001; OS: 15.6/12.9/9.3 months, p < 0.0001). Among patients with PD-L1 1-49%, CT plus ICI led to a longer PFS and OS (PFS: 8.9/5.8/4.2 months, p = 0.009; OS: 24.2/18.8/11.5 months, p = 0.03). In the cohort with PD-L1 ≥ 50%, CT plus ICI was still the best first-line treatment (PFS: 19.7/13.8/9.6 months, p = 0.033; OS: 27.2/19.6/14.9 months, p = 0.047). In driver gene-negative MLA with MPE, CT plus Bev or ICI better controlled MPE and significantly prolonged survival compared to CT alone. PD-L1 expression (negative/positive) may be a key factor influencing the choice of CT plus Bev or ICI.
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Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Derrame Pleural Maligno , Humanos , Bevacizumab , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Antígeno B7-H1 , Derrame Pleural Maligno/patología , Estudios Retrospectivos , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/genéticaRESUMEN
OBJECTIVES: To provide valuable insights for targeted cancer screening among high-risk patients, we analyzed the global and regional burden of neoplasms resulting from alcohol consumption between 1990 and 2019. METHODS: The information used in this study was collected from the Global Burden of Disease 2019 dataset. Initially, the database was used to extract details of mortality rates, disability-adjusted life years (DALYs), and the number of individuals affected by alcohol-related neoplasms (ARNs). Subsequently, the data were compared by cancer type, sex, age, region, and sociodemographic index. Furthermore, the study involved the calculation and comparison of estimated annual percentage changes in age-standardized DALYs rates (ASDRs) and mortality rates. RESULTS: The impact of alcohol on the burden of cancer varied by type of cancer, sex, age, and geographical location. Notably, males exhibited significantly higher ASDRs compared with females. Specifically, in 2019, alcohol emerged as the primary contributor to the number of DALYs associated with esophageal cancer, followed by liver cancer and colorectal cancer in men. Patients aged 50+ years exhibited a heightened rate of DALYs associated with ARNs. From 1990 to 2019, ASDRs among individuals with ARNs did not exhibit a decline in low-middle and low sociodemographic index regions. CONCLUSIONS: Alcohol consumption represents a significant risk factor for the burden of cancer, particularly within the realm of digestive system malignancies. Consequently, targeted cancer screening efforts should be directed toward the population that engages in alcohol drinking, with a particular focus on men aged 50 years and older, residing in economically disadvantaged areas.
Asunto(s)
Consumo de Bebidas Alcohólicas , Carga Global de Enfermedades , Neoplasias , Humanos , Masculino , Femenino , Persona de Mediana Edad , Neoplasias/epidemiología , Consumo de Bebidas Alcohólicas/epidemiología , Consumo de Bebidas Alcohólicas/efectos adversos , Anciano , Adulto , Años de Vida Ajustados por Discapacidad , Salud Global/estadística & datos numéricos , Adulto JovenRESUMEN
Bleeding from a visceral artery pseudoaneurysm (VAPA) is a rare but significant complication of bariatric surgery. Patients may present with gastrointestinal (GI) haemorrhage in the forms of haematemesis, melaena, haematochezia or haemodynamic compromise. Although CT angiogram, endoscopy and laparoscopy form essential parts of diagnostic assessment, small pseudoaneurysms with intermittent bleeding may be overlooked. We report the case of a man in his 40s who presented to the emergency department with massive GI bleeding and subsequent haemodynamic instability, secondary to a pseudoaneurysm from a vascular injury during a recent bariatric procedure. This case highlights the diagnostic challenges of obscure, intermittent bleeding involving the bypassed stomach with unremarkable investigation findings, and aims to raise awareness among clinicians in considering the less common postgastric-bypass complications.
Asunto(s)
Aneurisma Falso , Masculino , Humanos , Aneurisma Falso/etiología , Aneurisma Falso/complicaciones , Hemorragia Gastrointestinal/diagnóstico , Hematemesis , Melena/etiología , ArteriasRESUMEN
BACKGROUND: Autism spectrum disorder (henceforth autism) is a complex neurodevelopmental condition associated with differences in gray matter (GM) volume covariations, as reported in our previous study of the Longitudinal European Autism Project (LEAP) data. To make progress on the identification of potential neural markers and to validate the robustness of our previous findings, we aimed to replicate our results using data from the Enhancing Neuroimaging Genetics Through Meta-Analysis (ENIGMA) autism working group. METHODS: We studied 781 autistic and 927 non-autistic individuals (6-30 years, IQ ≥ 50), across 37 sites. Voxel-based morphometry was used to quantify GM volume as before. Subsequently, we used spatial maps of the two autism-related independent components (ICs) previously identified in the LEAP sample as templates for regression analyses to separately estimate the ENIGMA-participant loadings to each of these two ICs. Between-group differences in participants' loadings on each component were examined, and we additionally investigated the relation between participant loadings and autistic behaviors within the autism group. RESULTS: The two components of interest, previously identified in the LEAP dataset, showed significant between-group differences upon regressions into the ENIGMA cohort. The associated brain patterns were consistent with those found in the initial identification study. The first IC was primarily associated with increased volumes of bilateral insula, inferior frontal gyrus, orbitofrontal cortex, and caudate in the autism group relative to the control group (ß = 0.129, p = 0.013). The second IC was related to increased volumes of the bilateral amygdala, hippocampus, and parahippocampal gyrus in the autism group relative to non-autistic individuals (ß = 0.116, p = 0.024). However, when accounting for the site-by-group interaction effect, no significant main effect of the group can be identified (p > 0.590). We did not find significant univariate association between the brain measures and behavior in autism (p > 0.085). LIMITATIONS: The distributions of age, IQ, and sex between LEAP and ENIGMA are statistically different from each other. Owing to limited access to the behavioral data of the autism group, we were unable to further our understanding of the neural basis of behavioral dimensions of the sample. CONCLUSIONS: The current study is unable to fully replicate the autism-related brain patterns from LEAP in the ENIGMA cohort. The diverse group effects across ENIGMA sites demonstrate the challenges of generalizing the average findings of the GM covariation patterns to a large-scale cohort integrated retrospectively from multiple studies. Further analyses need to be conducted to gain additional insights into the generalizability of these two GM covariation patterns.