RESUMO

Introduction: Enterotoxigenic Escherichia coli (ETEC) is the main diarrhea-causing pathogen in children and young animals and has become a global health concern. Berberine is a type of "medicine and food homology" and has a long history of use in China, particularly in treating gastrointestinal disorders and bacterial diarrhea. Methods: In this study, we explored the effects of berberine on growth performance, intestinal inflammation, oxidative damage, and intestinal microbiota in a weaned piglet model of ETEC infection. Twenty-four piglets were randomly divided into four groups-a control group (fed a basal diet [BD] and infused with saline), a BD+ETEC group (fed a basal diet and infused with ETEC), a LB+ETEC group (fed a basal diet with 0.05% berberine and infused with ETEC infection), and a HB+ETEC group (fed a basal diet with 0.1% berberine and infused with ETEC). Results: Berberine significantly improved the final body weight (BW), average daily gain (ADG), and average daily feed intake (ADFI) (P<0.05) of piglets, and effectively decreased the incidence of diarrhea among the animals (P<0.05). Additionally, berberine significantly downregulated the expression levels of the genes encoding TNF-α, IL-1ß, IL-6, IL-8, TLR4, MyD88, NF-κB, IKKα, and IKKß in the small intestine of piglets (P<0.05). ETEC infection significantly upregulated the expression of genes coding for Nrf2, CAT, SOD1, GPX1, GST, NQO1, HO-1, GCLC, and GCLM in the small intestine of the animals (P<0.05). Berberine significantly upregulated 12 functional COG categories and 7 KEGG signaling pathways. A correlation analysis showed that berberine significantly increased the relative abundance of beneficial bacteria (Gemmiger, Pediococcus, Levilactobacillus, Clostridium, Lactiplantibacillus, Weissella, Enterococcus, Blautia, and Butyricicoccus) and decreased that of pathogenic bacteria (Prevotella, Streptococcus, Parabacteroides, Flavonifractor, Alloprevotella) known to be closely related to intestinal inflammation and oxidative stress in piglets. In conclusion, ETEC infection disrupted the intestinal microbiota in weaned piglets, upregulating the TLR4/MyD88/NF-κB and Nrf2 signaling pathways, and consequently leading to intestinal inflammation and oxidative stress-induced damage. Discussion: Our data indicated that berberine can optimize intestinal microbiota balance and modulate the TLR4/MyD88/NF-κB and Nrf2 signaling pathways, thus helping to alleviate intestinal inflammation and oxidative damage caused by ETEC infection in weaned piglets.

Assuntos

Berberina , Modelos Animais de Doenças , Escherichia coli Enterotoxigênica , Infecções por Escherichia coli , Microbioma Gastrointestinal , Estresse Oxidativo , Desmame , Animais , Berberina/farmacologia , Berberina/administração & dosagem , Suínos , Estresse Oxidativo/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Infecções por Escherichia coli/veterinária , Infecções por Escherichia coli/imunologia , Infecções por Escherichia coli/tratamento farmacológico , Diarreia/veterinária , Diarreia/tratamento farmacológico , Diarreia/microbiologia , Inflamação , Doenças dos Suínos/microbiologia , Doenças dos Suínos/tratamento farmacológico

RESUMO

Fabrication of well-dispersed thin graphene oxide (GO) films (GOFs) has always been a challenge. Herein, a quick preparation method for GOFs was developed using our homemade GO with a large lateral size. The film can be prepared in less than 2 h via a metal framework-induced self-assembly process. The thickness of the films can be as thin as ∼15.5 µm, which will be thinner with compression. When it is used as a flexible modification layer on the Zn metal for aqueous Zn-ion batteries, Zn can grow along the [010] direction in plane and stack orderly along the [002] direction even on the Cu substrate with GOF through epitaxial plating owing to negligible lattice mismatch between the (002) plane of Zn and the hexagonal ring [also (002) plane for graphite] of GO. Meanwhile, the rich O groups on the GO film can provide abundant zincophilic points and promote uniform distribution of Zn2+ around the anode. Finally, dendrite-free and dense Zn stripping/plating can be achieved and well remained. The GOF@Zn symmetric cell reveals long cyclic stability of 1300 h at 1 mA cm-2 and 1 mA h cm-2. It still can remain at 350 h even at a very high current density of 10 mA cm-2 accompanied by a high areal capacity of 10 mA h cm-2. With the same plating amount of 5 mA h cm-2, the thickness of the plated Zn is only ∼10 µm with GOF modification, very close to the theoretical value of 8.54 µm, much thinner than that without GOF (∼18 µm), indicating very dense deposition. Full cells assembled with the GOF@Zn anode and the MnO2 cathode exhibit a capacity retention rate of 71% over 1000 cycles at 0.7 A g-1, showing much better cycling performance than that using bare Zn.

RESUMO

BACKGROUND: Many uninsured patients do not receive Medicaid coverage until a cancer diagnosis, potentially delaying access to care for early cancer detection and treatment. We examine the association of Medicaid enrollment timing and patterns with survival among children and adolescents/young adults (AYAs) diagnosed with blood cancers, where disease onset can be acute and early detection is critical. METHODS: We identified 28,750 children and AYAs (0-39 years) newly diagnosed with blood cancers from the 2006-2013 SEER-Medicaid data. Enrollment patterns included continuous Medicaid (preceding through diagnosis), newly gained Medicaid (at/shortly after diagnosis), other noncontinuous Medicaid enrollment, and private/other insurance. We assessed cumulative incidence of death from diagnosis, censoring at last follow-up, five years post-diagnosis, or December 2018, whichever occurred first. Multivariable survival models estimated the association of insurance enrollment patterns with risk of death. RESULTS: One-fourth (26.1%) of the cohort were insured by Medicaid; of these, 41.1% had continuous Medicaid, 34.9% had newly gained Medicaid, and 24.0% had other noncontinuous enrollment. The cumulative incidence of all-cause death five-year post-diagnosis was highest in patients with newly gained Medicaid (30.2%, 95%CI = 28.4-31.9%), followed by other noncontinuous enrollment (23.2%, 95%CI = 21.3-25.2%), continuous Medicaid (20.5%, 95%CI = 19.1-21.9%), and private/other insurance (11.2%; 95%CI = 10.7-11.7%). In multivariable models, newly gained Medicaid was associated with a higher risk of all-cause (hazard ratio = 1.39, 95%CI = 1.27-1.53) and cancer-specific death (hazard ratio = 1.50, 95%CI = 1.35-1.68), compared to continuous Medicaid. CONCLUSIONS: Continuous Medicaid coverage is associated with survival benefits among pediatric and AYA patients diagnosed with blood cancers; however, less than half of Medicaid-insured patients have continuous coverage before diagnosis.

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Two-hierarchical nanostructures, characterized by two distinct configurations along the height direction, exhibit immense potential for applications in various fields due to their significantly enhanced controllable degree compared to single-order structures. However, due to the limitations imposed by planar technology, the realization of two-hierarchical nanostructures encounters huge challenges. In this work, we developed a one-step etching method based on inductively coupled plasma reactive ion etching for two-hierarchical nanostructures. Thanks to the shrinking effect of the Cr mask and the generation of a passivation layer during etching, the target materials experienced two different states from vertical etching to shrink etching. Consequently, the achieved two-hierarchical nanostructure configuration features a cross-section of an upper triangle and a lower rectangle, showing higher controllable degrees compared to the one-order ones. Both the mask pattern and etching parameters play crucial roles, by which two-hierarchical structures with diversiform shapes can be constructed controllably. This method for two-hierarchical nanostructures offers advantages including excellent control over structural properties, high processing efficiency, uniformity across large areas, and universality in materials. This developed strategy not only presents a simple and rapid nanofabrication platform for realizing optoelectronic devices, but also provides innovative ideas for designing the next generation of high-performance devices.

RESUMO

Receptor chromatography is an efficient analytical technique that combines the high separation ability of chromatography with the high specificity of receptors for drug recognition. In addition, this technique offers the advantages of active recognition, online separation, and convenient multidimensional target tracking. This strategy allows target active ingredients in complex systems, such as traditional Chinese medicines, to be efficiently screened and accurately identified. Furthermore, the interactions between ligands and immobilized proteins can be studied. To avoid a loss in function, receptor chromatography requires efficient, mild, and simple immobilization methods that do not damage the structure of the immobilized receptors. Improvements in the activity, stability, and ligand-recognition specificity of immobilized functional proteins can be achieved by selecting appropriate immobilization conditions. Notably, the protein immobilization method is not only closely related to the recognition ability of receptor chromatography but also determines the accuracy of the technique. Common methods for immobilizing functional proteins include physical adsorption, chemical reactions, biological affinity reactions, and click chemistry. Despite being easy to operate under mild reaction conditions, these methods have shortcomings, including poor reaction specificity and the necessity of using high-purity functional proteins to prepare chromatography columns. Maintaining the high activity of immobilized receptors and ensuring excellent identification and separation abilities are key challenges in the further development of receptor chromatography. In this work, these issues were addressed by introducing a specific bioorthogonal reaction involving haloalkane dehalogenase (Halo) and 6-chlorohexanoic acid for the immobilization of the α1A-adrenergic receptor (α1A-AR). Specifically, Halo-α1A-AR was immobilized on the surface of 6-chlorohexanoic acid-modified aminopropyl silica gel in one step. The stationary phase with immobilized Halo-α1A-AR was characterized using scanning electron microscopy. Moreover, the activity of the Halo-α1A-AR chromatographic column was evaluated using specific ligands (terazosin hydrochloride, phentolamine mesylate, tamsulosin hydrochloride, and urapidil) and nonspecific ligands (yohimbe and metoprolol) for α1A-AR. Halo-α1A-AR was successfully immobilized on the silica gel surface with good stability over 30 days, and the Halo-α1A-AR chromatographic column exhibited good ligand-recognition activity. The nonlinear chromatography results indicated that prazosin hydrochloride, terazosin hydrochloride, and urapidil interacted with immobilized Halo-α1A-AR through one type of binding site, with association constants of 3.85×105, 5.00×105, and 5.90×105L/mol, respectively. In contrast, phentolamine mesylate and tamsulosin hydrochloride interacted with immobilized Halo-α1A-AR through two types of binding site. The association constants with the high- and low-affinity binding sites were 3.12×106 and 6.01×105L/mol, respectively, for phentolamine mesylate and 9.98×105 and 0.21×105L/mol, respectively, for tamsulosin hydrochloride. Compared with the traditional carbonyldiimidazole method, the immobilization method developed in this work did not require receptor purification and thus minimized the loss of receptor activity. The affinity constants obtained with immobilized Halo-α1A-AR were consistent with the values determined for receptor-ligand binding in solution, indicating that the Halo-α1A-AR chromatography column is suitable for studying drug-protein interactions. This approach also provides a foundation for the efficient screening and accurate determination of target active ingredients in complex systems.

Assuntos

Hidrolases , Hidrolases/química , Receptores Adrenérgicos alfa 1/química , Receptores Adrenérgicos alfa 1/metabolismo , Humanos , Enzimas Imobilizadas/química

RESUMO

Antimicrobial peptides (AMPs) are a promising solution for treating antibiotic-resistant pathogens. However, efficient generation of diverse AMPs without prior knowledge of peptide structures or sequence alignments remains a challenge. Here, ProT-Diff is introduced, a modularized deep generative approach that combines a pretrained protein language model with a diffusion model for the de novo generation of AMPs sequences. ProT-Diff generates thousands of AMPs with diverse lengths and structures within a few hours. After silico physicochemical screening, 45 peptides are selected for experimental validation. Forty-four peptides showed antimicrobial activity against both gram-positive or gram-negative bacteria. Among broad-spectrum peptides, AMP_2 exhibited potent antimicrobial activity, low hemolysis, and minimal cytotoxicity. An in vivo assessment demonstrated its effectiveness against a drug-resistant E. coli strain in acute peritonitis. This study not only introduces a viable and user-friendly strategy for de novo generation of antimicrobial peptides, but also provides potential antimicrobial drug candidates with excellent activity. It is believed that this study will facilitate the development of other peptide-based drug candidates in the future, as well as proteins with tailored characteristics.

RESUMO

PURPOSE: Many patients with cancer do not gain Medicaid coverage until a cancer diagnosis, which can reduce access to early cancer detection and timely treatment, potentially driving inferior survival. Little is known about whether continuous Medicaid coverage prediagnosis through postdiagnosis (v gaining Medicaid at/after diagnosis) provides survival benefits for pediatric/adolescent oncology patients. MATERIALS AND METHODS: We identified patients newly diagnosed with cancer at age 21 years or younger in a large pediatric health system between 2007 and 2016. Electronic medical records (EMRs) were linked to Medicaid administrative data to differentiate insurance continuity patterns during the 6 months preceding through the 6 months after cancer diagnosis (assessment window): continuous Medicaid, newly gained Medicaid (at or after diagnosis), and other Medicaid enrollment patterns. For patients not linked to Medicaid data, we used EMR-reported insurance types at diagnosis. We followed patients from 6 months postdiagnosis up to 5 years, death, or December 2020, whichever came first. Multivariable regressions estimated all-cause and cancer-specific survival, controlling for sociodemographic and cancer-related factors. RESULTS: Among 1,800 patients included in the analysis, 1,293 (71.8%) had some Medicaid enrollment during the assessment window; among them, 47.6% had continuous Medicaid and 36.3% had newly gained Medicaid. Patients not linked with Medicaid data had private (26.9%) or other/no insurance (1.2%) at diagnosis. Compared with patients with continuous Medicaid, those with newly gained Medicaid had higher risks of all-cause death (hazard ratio [HR], 1.41 [95% CI, 1.10 to 1.81]; P = .008) and cancer-specific death (HR, 1.46 [95% CI, 1.12 to 1.90]; P = .005). CONCLUSION: Continuous Medicaid coverage throughout cancer diagnosis is associated with survival benefits for pediatric/adolescent patients. This finding has critical implications as millions of American individuals have been losing coverage since the unwinding of the Medicaid Continuous Enrollment Provision.

RESUMO

The electrooxidation of catalyst surfaces is across various electrocatalytic reactions, directly impacting their activity, stability and selectivity. Precisely characterizing the electrooxidation on well-defined surfaces is essential to understanding electrocatalytic reactions comprehensively. Herein, we employed in situ Raman spectroscopy to monitor the electrooxidation process of palladium single crystal. Our findings reveal that the Pd surface's initial electrooxidation process involves forming *OH intermediate and ClO4 - ions facilitate the deprotonation process, leading to the formation of PdOx. Subsequently, under deep electrooxidation potential range, the oxygen atoms within PdOx contribute to creating surface-bound peroxide species, ultimately resulting in oxygen generation. The adsorption strength of *OH and the coverage of ClO4 - can be adjusted by the controllable electronic effect, resulting in different oxidation rates. This study offers valuable insights into elucidating the electrooxidation mechanisms underlying a range of electrocatalytic reactions, thereby contributing to the rational design of catalysts.

RESUMO

Ischemic lesion segmentation and the time since stroke (TSS) onset classification from paired multi-modal MRI imaging of unwitnessed acute ischemic stroke (AIS) patients is crucial, which supports tissue plasminogen activator (tPA) thrombolysis decision-making. Deep learning methods demonstrate superiority in TSS classification. However, they often overfit task-irrelevant features due to insufficient paired labeled data, resulting in poor generalization. We observed that unpaired data are readily available and inherently carry task-relevant cues, but are less often considered and explored. Based on this, in this paper, we propose to fully excavate the potential of unpaired unlabeled data and use them to facilitate the downstream AIS analysis task. We first analyze the utility of features at the varied grain and propose a multi-grained contrastive learning (MGCL) framework to learn task-related prior representations from both coarse-grained and fine-grained levels. The former can learn global prior representations to enhance the location ability for the ischemic lesions and perceive the healthy surroundings, while the latter can learn local prior representations to enhance the perception ability for semantic relation between the ischemic lesion and other health regions. To better transfer and utilize the learned task-related representation, we designed a novel multi-task framework to simultaneously achieve ischemic lesion segmentation and TSS classification with limited labeled data. In addition, a multi-modal region-related feature fusion module is proposed to enable the feature correlation and synergy between multi-modal deep image features for more accurate TSS decision-making. Extensive experiments on the large-scale multi-center MRI dataset demonstrate the superiority of the proposed framework. Therefore, it is promising that it helps better stroke evaluation and treatment decision-making.

Assuntos

Aprendizado Profundo , AVC Isquêmico , Imageamento por Ressonância Magnética , Humanos , AVC Isquêmico/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Interpretação de Imagem Assistida por Computador/métodos

RESUMO

Functional protein immobilization forms the basis for bio-detections. A series of one-point, site-specific immobilization methods have been developed, however, it still remains as a challenge how to avoid the proteins to move in all directions as well as conveniently regenerate the bio-devices. Herein, we have developed a bivalent affinity binding-inspired method for PPARγ immobilization using DNA aptamer and nickel-nitrilotriacetic acid (Ni2+-NTA) chelation. The specific DNA aptamer (Apt 2) was selected by an on-column systematic evolution of ligands by exponential enrichment (SELEX) method with affinity of (1.57 ± 0.15) × 105 M-1, determined by isothermal titration calorimetry (ITC). Apt 2 and nickel-nitrilotriacetic acid (Ni2+-NTA) were modified on macroporous silica gels via L-α-allylglycine as a linker. They respectively interacted with PPARγ and 6×His tag via bivalent affinity binding for the receptor immobilization. After comprehensive surface characterization, PPARγ was proved to be successful immobilized. Chromatographic studies revealed that the immobilized PPARγ has conformation selectivity, which discriminated agonist and antagonist of the receptor. Ligand-binding parameters (affinity and rate constant) of four agonists (rosiglitazone, pioglitazone, troglitazone, and magnolol) with PPARγ were determined. Troglitazone showed the lowest dissociation rate constant. The binding affinities (3.28 × 107, 1.91 × 106, 2.25 × 107, and 2.43 × 107 M-1) were highly consistent with the data obtained using purified receptor in solution (2.16 × 107, 4.52 × 106, 1.20 × 107, and 1.56 × 107 M-1), offering reliable bio-detection method for PPARγ and its ligands. Due to the biocompatibility of nuclear receptor with DNA, it is conceivable that the bivalent affinity-based method will be a general method for the immobilization of other nuclear receptors, which may provide selective conformation and improved ligand-binding activity for the receptors.

Assuntos

Aptâmeros de Nucleotídeos , PPAR gama , PPAR gama/química , PPAR gama/metabolismo , Ligantes , Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/metabolismo , Ligação Proteica , Proteínas Imobilizadas/química , Proteínas Imobilizadas/metabolismo , Ácido Nitrilotriacético/química , Ácido Nitrilotriacético/análogos & derivados , Humanos , Calorimetria

RESUMO

Nitrification is highly crucial for both anammox systems and the global nitrogen cycle. The discovery of complete ammonia oxidation (comammox) challenges the inherent concept of nitrification as a two-step process. Its wide distribution, adaptability to low substrate environments, low sludge production, and low greenhouse gas emissions may make it a promising new nitrogen removal treatment process. Meanwhile, anammox technology is considered the most suitable process for future wastewater treatment. The diverse metabolic capabilities and similar ecological niches of comammox bacteria and anammox bacteria are expected to achieve synergistic nitrogen removal within a single system. However, previous studies have overlooked the existence of comammox, and it is necessary to re-evaluate the conclusions drawn. This paper outlined the ecophysiological characteristics of comammox bacteria and summarized the environmental factors affecting their growth. Furthermore, it focused on the enrichment, regulatory strategies, and nitrogen removal mechanisms of comammox and anammox, with a comparative analysis of hydroxylamine, a particular intermediate product. Overall, this is the first critical overview of the conclusions drawn from the last few years of research on comammox-anammox, highlighting possible next steps for research.

Assuntos

Amônia , Nitrificação , Nitrogênio , Oxirredução , Eliminação de Resíduos Líquidos , Nitrogênio/metabolismo , Eliminação de Resíduos Líquidos/métodos , Amônia/metabolismo , Bactérias/metabolismo , Águas Residuárias , Reatores Biológicos/microbiologia , Anaerobiose

RESUMO

Microplastics (MPs) are prevalent in diverse environmental settings, posing a threat to plants and animals in the water and soil and even human health, and eventually converged in wastewater treatment plants (WWTPs), threatening the stable operation of anaerobic ammonium oxidation (anammox). Consequently, a comprehensive summary of their impacts on anammox and the underlying mechanisms must be provided. This article reviews the sources and removal efficiency of MPs in WWTPs, as well as the influencing factors and mechanisms on anammox systems. Numerous studies have demonstrated that MPs in the environment can enter WWTPs via domestic wastewater, rainwater, and industrial wastewater discharges. More than 90% of these MPs are found to accumulate in the sludge following their passage through the treatment units of the WWTPs, affecting the characteristics of the sludge and the efficiency of the microorganisms treating the wastewater. The key parameters of MPs, encompassing concentration, particle size, and type, exert a notable influence on the nitrogen removal efficiency, physicochemical characteristics of sludge, and microbial community structure in anammox systems. It is noteworthy that extracellular polymer secretion (EPS) and reactive oxygen stress (ROS) are important impact mechanisms by which MPs exposure affects anammox systems. In addition, the influence of MPs exposure on the microbial community structure of anammox cells represents a crucial mechanism that demands attention. Future research endeavors will delve into additional crucial parameters of MPs, such as shape and aging, to investigate their effects and mechanisms on anammox. Furthermore, the effective mitigation strategies will also be developed. The paper provides a fresh insight to reveal the influences of MPs exposure on the anammox process and its influence mechanisms, and lays the groundwork for further exploration into the influence of MPs on anammox and potential mitigation strategies.

Assuntos

Microplásticos , Oxirredução , Compostos de Amônio/metabolismo , Anaerobiose , Eliminação de Resíduos Líquidos/métodos , Águas Residuárias/química , Esgotos

RESUMO

BACKGROUND: Myasthenia gravis (MG) is a long-term autoimmune disorder that affects the neuromuscular junction, causing muscle weakness and fatigue as its primary clinical features. Vitamin D is crucial for both the autoimmune response and skeletal muscle function. CASE PRESENTATION: Here, we presented a case report documenting the substantial improvement in symptoms experienced by a patient who underwent subtotal gastrectomy for gastric cancer following high-dose Vitamin D supplementation. The patient developed generalized MG two months after the surgery and did not respond adequately to pyridostigmine therapy, experiencing a progressive deterioration of the condition. A significant reduction in vitamin D concentration was observed following subtotal gastrectomy. In response, high-dose vitamin D supplementation was administered to the patient. Within one week of treatment, swallowing symptoms improved, enabling the consumption of a small amount of liquid food. By the second week, substantial swallowing and neck function improvements were evident. After one month, the patient regained the ability to straighten the neck while walking and consumed a regular diet despite persistent difficulties chewing hard food. CONCLUSIONS: This case underscores the therapeutic potential of vitamin D in alleviating MG symptoms, particularly in individuals with compromised vitamin D levels following gastrectomy. The observed improvements present a new perspective on the possible involvement of vitamin D supplementation in the management of postoperative MG cases.

Assuntos

Gastrectomia , Miastenia Gravis , Vitamina D , Humanos , Suplementos Nutricionais , Gastrectomia/efeitos adversos , Miastenia Gravis/cirurgia , Miastenia Gravis/tratamento farmacológico , Neoplasias Gástricas/cirurgia , Vitamina D/uso terapêutico , Vitamina D/administração & dosagem

RESUMO

BACKGROUND: Penile squamous cell carcinoma (PSCC) carries significant morbidity and mortality. Literature is limited regarding prognostic factors, especially prognostic factors for development of metastasis. OBJECTIVES: To identify independent prognostic factors associated with poor outcomes, defined as local recurrence (LR), metastasis and disease-specific death (DSD) in clinically node-negative PSCC undergoing local therapy. METHODS: Thirty-two-year Retrospective Multicenter Cohort Study of 265 patients with histologically diagnosed PSCC at three tertiary care centres. Predictive models based on patient or tumour characteristics were developed. RESULTS: Local recurrence occurred in 56 patients, metastasis in 52 patients and DSD in 40 patients. In multivariable models, the following five factors were independent prognostic factors based on subhazard ratio (SHR): history of balanitis (LR SHR: 2.3; 95% CI 1.2-4.2), poor differentiation (metastasis SHR 1.9; 95% CI 1.0-3.6), invasion into the corpora (metastasis SHR: 3.0; 95% CI 1.5-5.8 and DSD SHR: 4.5; 95% CI 1.7-12.1), perineural invasion (PNI) (metastasis SHR: 2.8; 95% CI 1.4-5.5 and DSD SHR: 3.5; 95% CI, 1.6-7.8) and a history of phimosis (DSD SHR: 2.5; 95% CI 1.2-5.3). The 5-year cumulative incidence of metastasis was higher for tumours with PNI [cumulative incidence function (CIF) = 55%, 95% CI 38-75 vs. CIF 15%, 95% CI 11-22], corporal invasion (CIF: 35%, 95% CI 26-47 vs. 12%, 95% CI 7-19) and poorly differentiated tumours (CIF = 46%, 95% CI 31-64 vs. CIF 15%, 95% CI 11-22). CONCLUSIONS: History of balanitis, history of phimosis, PNI, corporal invasion and poor differentiation are independent risk factors associated with poor outcomes. Since poor differentiation and PNI currently constitute only T1b disease, prognostic staging can likely be improved.

RESUMO

As a result of the lack of modern techniques, the study of Tibetan medicine has been hindered in identifying bioactive compounds. Herein, we established a chromatographic approach using an immobilized angiotensin II type 1 receptor (AT1R) via a one-step method triggered by haloalkane dehalogenase. The bioactive compounds from Choerospondias axillaris (Guangzao) were screened and identified using the immobilized AT1R followed by MS. Frontal analysis (FA) and adsorption energy distribution (AED) were used to evaluate the association constants. Molecular docking was used to investigate the binding configurations, and the surface efficiency index, binding efficiency index, and ligand-lipophilicity efficiency (LLE) were calculated to assess the drug-like properties. The results identified naringenin, pinocembrin, and chrysin as the compounds that specifically bind to AT1R in Guangzao. FA and AED confirmed that there is only one type of binding site between these compounds and AT1R. The association constants were (2.40 ± 0.02) × 104 M-1 for naringenin (5.22 ± 0.26) × 104 M-1 for pinocembrin, and (4.27 ± 0.14) × 104 M-1 for chrysin, respectively. These compounds can bind with AT1R through the orthosteric binding pocket. Naringenin exhibited better LLE than pinocembrin and chrysin. These results confirmed the feasibility of using the immobilized AT1R column for screening and analyzing bioactive compounds in Tibetan medicines.

Assuntos

Simulação de Acoplamento Molecular , Extratos Vegetais , Receptor Tipo 1 de Angiotensina , Extratos Vegetais/química , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 1 de Angiotensina/química , Cromatografia Líquida de Alta Pressão/métodos

RESUMO

Luteolin, a monomeric substance, is a natural product of the Brucea javanica (BJ) plant. Brucea javanica oil emulsion injection (BJOEI) is a proprietary Chinese medicine purified from BJ that is widely used clinically as an anti-tumor treatment. Although a growing body of research suggests that luteolin and BJOEI have anti-tumor effects, the molecular mechanism of action has not been fully elucidated. In this study, through molecular docking technology, we found that luteolin can interact directly with GPSM2 and regulate the FoxO signaling pathway through GPSM2. In addition, the inhibitory effect of luteolin on colon adenocarcinoma (COAD) cells was found to be offset by knockdown of GPSM2. In contrast, the anti-proliferative effects of luteolin could be notably reversed by overexpression of GPSM2. The results reveal that GPSM2 is crucial in luteolin-mediated anti-proliferative effects. The mediation of anti-proliferative effects by GPSM2 has also been indirectly demonstrated in RKO and SW480 xenograft mice models. In addition, we verified that BJOEI inhibits the progression of COAD by mediating GPSM2 and regulating the FoxO signaling pathway. We also found that BJOEI achieved a better anti-tumor effect when combined with fluorouracil injection. Collectively, our data show that the anti-tumor effects of BJOEI and luteolin on COAD are GPSM2-dependent and downregulating the expression of GPSM2 to regulate the FoxO signaling pathway may be an effective way to treat COAD.

Assuntos

Adenocarcinoma , Proliferação de Células , Neoplasias do Colo , Fluoruracila , Luteolina , Camundongos Nus , Luteolina/farmacologia , Humanos , Animais , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Neoplasias do Colo/metabolismo , Fluoruracila/farmacologia , Linhagem Celular Tumoral , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Adenocarcinoma/metabolismo , Proliferação de Células/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Endogâmicos BALB C , Transdução de Sinais/efeitos dos fármacos , Camundongos , Produtos Biológicos/farmacologia , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/uso terapêutico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Simulação de Acoplamento Molecular

RESUMO

Programmed death-1 (PD-1) acts as a T cell checkpoint and is important in controlling T cell exhaustion. Blocking the intercommunication across PD-1 and PD-L1 is promising for advanced lung cancer treatment. However, the response rate requires being strengthened. This study aimed to determine whether the combination treatment of Qingfei mixture (QFM) and PD-1 inhibitor could improve the sensitivity of monoclonal antibody by regulating STAT1/IDO1-mediated tryptophan (Trp)-kynurenine (Kyn) pathway. The in vivo imaging system, immunofluorescence, hematoxylin-eosin staining, TUNEL, flow cytometry, HPLC, and ELISA were used to estimate the anti-tumor effects in LLC-luc tumor-bearing C57BL/6 mice treated with QFM, PD-1 inhibitor, 2-NP (enhancer of STAT1 transcription), and FICZ (AhR agonist) alone or in combination. IFN-γ-mediated A549 and LLC cells were treated with QFM-containing serum and fludarabine (FLU, STAT1 inhibitor), and cell viability, apoptosis, and Kyn content were then evaluated using CCK-8 assays, flow cytometry, and HPLC assays, respectively. Additionally, the expressions of STAT1, IDO1, AhR, NFATc1, TRIP12, PD-1, and PD-L1 were measured in vivo and in vitro. We found QFM increased the anti-cancer actions of PD-1 inhibitors by increasing the CD8+IFNγ+ T cells infiltration and decreasing the ratio of Kyn/Trp. Besides, QFM-containing serum suppressed the proliferation and promoted apoptosis in A549 and LLC cells, meanwhile, FLU boosted the effects of QFM-containing serum. Moreover, the suppression of tumor growth in the combination therapy was attenuated in the mice receiving 2-NP or FICZ. The occurrence of the above results was accompanied by a decrease in STAT1, IDO1, AhR, PD-1, and PD-L1 expressions. Collectively, the findings suggested that QFM may increase the influences of PD-1 inhibitors at least partially by blocking the STAT1/IDO1-mediated tryptophan-kynurenine pathway in lung cancer.

RESUMO

BACKGROUND: The Affordable Care Act (ACA) increased private nonemployer health insurance options, expanded Medicaid eligibility, and provided preexisting health condition protections. We evaluated insurance coverage among long-term adult survivors of childhood cancer pre- and post-ACA implementation. METHODS: Using the multicenter Childhood Cancer Survivor Study, we included participants from 2 cross-sectional surveys: pre-ACA (2007-2009; survivors: n = 7505; siblings: n = 2175) and post-ACA (2017-2019; survivors: n = 4030; siblings: n = 987). A subset completed both surveys (1840 survivors; 646 siblings). Multivariable regression models compared post-ACA insurance coverage and type (private, public, uninsured) between survivors and siblings and identified associated demographic and clinical factors. Multinomial models compared gaining and losing insurance vs staying the same among survivors and siblings who participated in both surveys. RESULTS: The proportion with insurance was higher post-ACA (survivors pre-ACA 89.1% to post-ACA 92.0% [+2.9%]; siblings pre-ACA 90.9% to post-ACA 95.3% [+4.4%]). Post-ACA insurance increase in coverage was higher among those aged 18-25 years (survivors: +15.8% vs +2.3% or less ages 26 years and older; siblings +17.8% vs +4.2% or less ages 26 years and older). Survivors were more likely to have public insurance than siblings post-ACA (18.4% vs 6.9%; odds ratio [OR] = 1.7, 95% confidence interval [CI] = 1.1 to 2.6). Survivors with severe chronic conditions (OR = 4.7, 95% CI = 3.0 to 7.3) and those living in Medicaid expansion states (OR = 2.4, 95% CI = 1.7 to 3.4) had increased odds of public insurance coverage post-ACA. Among the subset completing both surveys, low- and mid-income survivors (<$40 000 and <$60 000, respectively) experienced insurance losses and gains in reference to highest household income survivors (≥$100 000), relative to odds of keeping the same insurance status. CONCLUSIONS: Post-ACA, more childhood cancer survivors and siblings had health insurance, although disparities remain in coverage.

Assuntos

Sobreviventes de Câncer , Cobertura do Seguro , Seguro Saúde , Neoplasias , Patient Protection and Affordable Care Act , Humanos , Sobreviventes de Câncer/estatística & dados numéricos , Feminino , Masculino , Estados Unidos/epidemiologia , Cobertura do Seguro/estatística & dados numéricos , Adulto , Seguro Saúde/estatística & dados numéricos , Neoplasias/terapia , Neoplasias/economia , Neoplasias/epidemiologia , Estudos Transversais , Adolescente , Criança , Adulto Jovem , Medicaid/estatística & dados numéricos , Irmãos , Pessoas sem Cobertura de Seguro de Saúde/estatística & dados numéricos , Pessoa de Meia-Idade

RESUMO

Vertebral artery dissection is a rare pathology that can cause ischemic stroke in young people. Cervical massage, especially improper pulling manipulation, is a cause of vertebral artery dissection. We present a case of 32-year-old woman who developed acute multiple posterior circulation ischemic cerebral infarctions as a result of left vertebral artery V4 segment dissection after receiving neck massage. She underwent emergency vertebral artery stent implantation at the site of the dissection. Symptoms were relieved the day after treatment. The patient recovered without adverse complications or endovascular restenosis in the following year.

Assuntos

Infarto Cerebral , Massagem , Stents , Dissecação da Artéria Vertebral , Humanos , Feminino , Dissecação da Artéria Vertebral/diagnóstico por imagem , Dissecação da Artéria Vertebral/etiologia , Dissecação da Artéria Vertebral/cirurgia , Adulto , Stents/efeitos adversos , Massagem/efeitos adversos , Infarto Cerebral/etiologia , Infarto Cerebral/diagnóstico por imagem , Artéria Vertebral/diagnóstico por imagem , Artéria Vertebral/cirurgia