RESUMO
BACKGROUND: To systematically evaluate the safety and efficacy of Deucravacitinib for moderate to severe plaque psoriasis. MATERIALS AND METHODS: Randomized controlled trials (RCTs) of Deucravacitinib for moderate to severe plaque psoriasis in PubMed, Cochrane Library, Embase, and Web of Science were searched from database establishment to April 2023. Literature quality was independently evaluated by two investigators using the Cochrane risk-of-bias assessment tool, and the systematic analysis was made using StateSE15 and RevMan 5.3 software. RESULTS: Four RCTs were included, including 1751 patients with moderate to severe plaque psoriasis. Meta-analysis showed that the differences in efficacy and adverse events (AEs) between the Deucravacitinib group and placebo group were significant (p < 0.05). The patients in the Deucravacitinib group took orally 3-12 mg daily for 12 sequential weeks or 6 mg daily for 52 sequential weeks. Psoriasis Area and Severity Index (PASI) reduced by 75% (PASI 75), (PASI 90), and (PASI 100), static Physician Global Assessment (sPGA) of 0 or 1 (sPGA 0/1), Dermatology Life Quality Index of 0 or 1 (DLQI 0/1), and Psoriasis Symptoms and Signs Diary (PSSD) were significantly higher in the Deucravacitinib group compared to the placebo group, with significant differences (p < 0.05). The most frequently encountered AEs after treatment in the Deucravacitinib group was nasopharyngitis. CONCLUSION: Oral administration of Deucravacitinib is effective for moderate to severe plaque psoriasis. Attention should be paid to the occurrence of AEs, and more RCTs are required to evaluate the relationship between the dose and safety and efficacy.
Assuntos
Psoríase , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos , Psoríase/tratamento farmacológico , Índice de Gravidade de Doença , Fármacos Dermatológicos/efeitos adversos , Fármacos Dermatológicos/uso terapêutico , Fármacos Dermatológicos/administração & dosagem , Resultado do TratamentoRESUMO
BACKGROUND: Ear keloids, often resulting from ear piercing or other traumas, significantly alter appearance, adversely impacting patients' quality of life and psychological well-being. Thus, developing an effective and esthetically pleasing surgical repair technique is crucial for enhancing patient quality of life. METHODS: This study introduces a novel tripartite surgical approach, which includes arcuate incision design, blind dissection for scar flap, and centrifugal keloid core serial shave excision (ABC for short). This technique is particularly suited for keloids induced by ear piercing that are inoperable for direct suturing or where direct suturing significantly alters the ear contour. RESULTS: In this study, 17 patients underwent the surgical treatment without observing special complications such as infection or necrosis. Long-term postoperative follow-up demonstrated good restoration of the ear contour, with only one case of recurrence. Patients expressed satisfaction with both the surgical process and outcomes. CONCLUSIONS: The triple surgical technique (ABC surgery method) for treating auricular keloids has demonstrated excellent repair results, significantly improving auricle shape. Despite relying on the surgeon's experience, keloid characteristics, and patient comorbidities, it provides an effective treatment option. When combined with local radiotherapy, the recurrence rate is also significantly controlled. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
RESUMO
BACKGROUND: During drug development, it is essential to gather information about the change of clinical exposure of a drug (object) due to the pharmacokinetic (PK) drug-drug interactions (DDIs) with another drug (precipitant). While many natural language processing (NLP) methods for DDI have been published, most were designed to evaluate if (and what kind of) DDI relationships exist in the text, without identifying the direction of DDI (object vs. precipitant drug). Here we present a method for the automatic identification of the directionality of a PK DDI from literature or drug labels. METHODS: We reannotated the Text Analysis Conference (TAC) DDI track 2019 corpus for identifying the direction of a PK DDI and evaluated the performance of a fine-tuned BioBERT model on this task by following the training and validation steps prespecified by TAC. RESULTS: This initial attempt showed the model achieved an F-score of 0.82 in identifying sentences as containing PK DDI and an F-score of 0.97 in identifying object versus precipitant drugs in those sentences. DISCUSSION AND CONCLUSION: Despite a growing list of NLP methods for DDI extraction, most of them use a common set of corpora to perform general purpose tasks (e.g., classifying a sentence into one of several fixed DDI categories). There is a lack of coordination between the drug development and biomedical informatics method development community to develop corpora and methods to perform specific tasks (e.g., extract clinical exposure changes due to PK DDI). We hope that our effort can encourage such a coordination so that more "fit for purpose" NLP methods could be developed and used to facilitate the drug development process.
Assuntos
Aprendizado Profundo , Processamento de Linguagem Natural , Interações Medicamentosas , Mineração de Dados/métodos , IdiomaRESUMO
Importance: Opioids can cause severe respiratory depression by suppressing feedback mechanisms that increase ventilation in response to hypercapnia. Following the addition of boxed warnings to benzodiazepine and opioid products about increased respiratory depression risk with simultaneous use, the US Food and Drug Administration evaluated whether other drugs that might be used in place of benzodiazepines may cause similar effects. Objective: To study whether combining paroxetine or quetiapine with oxycodone, compared with oxycodone alone, decreases the ventilatory response to hypercapnia. Design, Setting, and Participants: Randomized, double-blind, crossover clinical trial at a clinical pharmacology unit (West Bend, Wisconsin) with 25 healthy participants from January 2021 through May 25, 2021. Interventions: Oxycodone 10 mg on days 1 and 5 and the following in a randomized order for 5 days: paroxetine 40 mg daily, quetiapine twice daily (increasing daily doses from 100 mg to 400 mg), or placebo. Main Outcomes and Measures: Ventilation at end-tidal carbon dioxide of 55 mm Hg (hypercapnic ventilation) using rebreathing methodology assessed for paroxetine or quetiapine with oxycodone, compared with placebo and oxycodone, on days 1 and 5 (primary) and for paroxetine or quetiapine alone compared with placebo on day 4 (secondary). Results: Among 25 participants (median age, 35 years [IQR, 30-40 years]; 11 female [44%]), 19 (76%) completed the trial. The mean hypercapnic ventilation was significantly decreased with paroxetine plus oxycodone vs placebo plus oxycodone on day 1 (29.2 vs 34.1 L/min; mean difference [MD], -4.9 L/min [1-sided 97.5% CI, -∞ to -0.6]; P = .01) and day 5 (25.1 vs 35.3 L/min; MD, -10.2 L/min [1-sided 97.5% CI, -∞ to -6.3]; P < .001) but was not significantly decreased with quetiapine plus oxycodone vs placebo plus oxycodone on day 1 (33.0 vs 34.1 L/min; MD, -1.2 L/min [1-sided 97.5% CI, -∞ to 2.8]; P = .28) or on day 5 (34.7 vs 35.3 L/min; MD, -0.6 L/min [1-sided 97.5% CI, -∞ to 3.2]; P = .37). As a secondary outcome, mean hypercapnic ventilation was significantly decreased on day 4 with paroxetine alone vs placebo (32.4 vs 41.7 L/min; MD, -9.3 L/min [1-sided 97.5% CI, -∞ to -3.9]; P < .001), but not with quetiapine alone vs placebo (42.8 vs 41.7 L/min; MD, 1.1 L/min [1-sided 97.5% CI, -∞ to 6.4]; P = .67). No drug-related serious adverse events were reported. Conclusions and Relevance: In this preliminary study involving healthy participants, paroxetine combined with oxycodone, compared with oxycodone alone, significantly decreased the ventilatory response to hypercapnia on days 1 and 5, whereas quetiapine combined with oxycodone did not cause such an effect. Additional investigation is needed to characterize the effects after longer-term treatment and to determine the clinical relevance of these findings. Trial Registration: ClinicalTrials.gov Identifier: NCT04310579.
Assuntos
Analgésicos Opioides , Antidepressivos , Oxicodona , Paroxetina , Fumarato de Quetiapina , Insuficiência Respiratória , Adulto , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/farmacologia , Antidepressivos/efeitos adversos , Antidepressivos/farmacologia , Benzodiazepinas/efeitos adversos , Benzodiazepinas/farmacologia , Dióxido de Carbono/análise , Método Duplo-Cego , Feminino , Humanos , Hipercapnia/etiologia , Oxicodona/efeitos adversos , Oxicodona/farmacologia , Paroxetina/efeitos adversos , Paroxetina/farmacologia , Fumarato de Quetiapina/efeitos adversos , Fumarato de Quetiapina/farmacologia , Respiração/efeitos dos fármacos , Insuficiência Respiratória/induzido quimicamente , Insuficiência Respiratória/diagnósticoRESUMO
BACKGROUND This study explored the clinical effects of whole-process digitalization (WD)-assisted immediate implant placement (IIP) and immediate restoration (IR) in the aesthetic zone and clarified the clinical procedures. MATERIAL AND METHODS Patients who received maxillary aesthetic region IIP and IR treatment were randomly distributed into WD-assisted and conventional groups. Postoperative assessment included implant accuracy, marginal bone loss, aesthetic evaluation, and patient satisfaction evaluation. The aesthetic evaluation included visual analog score (VAS), pink aesthetic score (PES), and white aesthetic score (WES). Numerical data, measurement data, and grade data were analyzed by χ² test, t test, and Mann-Whitney U test. RESULTS The WD-assisted group exhibited decreased implant accuracy, including coronal deviation, apical deviation, angular deviation, and depth deviation, compared with the conventional group (P<0.05). The marginal bone loss in both the mesiodistal direction and the buccolingual direction were significantly lower in the WD-assisted group than in the conventional group (P<0.05). The VAS, PES, and WES were all significantly higher in the WD-assisted group than in the conventional group at 3, 6, and 12 months after surgery (P<0.05). Patients in the WD-assisted group also reported a higher satisfaction level than those in the conventional group (P<0.05). CONCLUSIONS WD-assisted IIP and IR treatment in the aesthetic zone increased implant accuracy, decreased marginal bone loss, improved aesthetic effect, and increased patient satisfaction compared with conventional treatment. Therefore, WD-assisted IIP and IR treatment constitutes a promising approach in clinical oral implantology.
Assuntos
Implantação Dentária/métodos , Implantação Dentária/normas , Implantes Dentários , Estética Dentária , Adulto , Feminino , Humanos , Imageamento Tridimensional , Masculino , Maxila/cirurgia , Satisfação do Paciente , Radiografia , Cirurgia Assistida por Computador/métodos , Cirurgia Assistida por Computador/normas , Fatores de Tempo , Resultado do TratamentoRESUMO
INTRODUCTION: hERG block potency is widely used to calculate a drug's safety margin against its torsadogenic potential. Previous studies are confounded by use of different patch clamp electrophysiology protocols and a lack of statistical quantification of experimental variability. Since the new cardiac safety paradigm being discussed by the International Council for Harmonisation promotes a tighter integration of nonclinical and clinical data for torsadogenic risk assessment, a more systematic approach to estimate the hERG block potency and safety margin is needed. METHODS: A cross-industry study was performed to collect hERG data on 28 drugs with known torsadogenic risk using a standardized experimental protocol. A Bayesian hierarchical modeling (BHM) approach was used to assess the hERG block potency of these drugs by quantifying both the inter-site and intra-site variability. A modeling and simulation study was also done to evaluate protocol-dependent changes in hERG potency estimates. RESULTS: A systematic approach to estimate hERG block potency is established. The impact of choosing a safety margin threshold on torsadogenic risk evaluation is explored based on the posterior distributions of hERG potency estimated by this method. The modeling and simulation results suggest any potency estimate is specific to the protocol used. DISCUSSION: This methodology can estimate hERG block potency specific to a given voltage protocol. The relationship between safety margin thresholds and torsadogenic risk predictivity suggests the threshold should be tailored to each specific context of use, and safety margin evaluation may need to be integrated with other information to form a more comprehensive risk assessment.
Assuntos
Canal de Potássio ERG1/antagonistas & inibidores , Medição de Risco/métodos , Torsades de Pointes/induzido quimicamente , Teorema de Bayes , Simulação por Computador , Humanos , Modelos Biológicos , Técnicas de Patch-Clamp , Bloqueadores dos Canais de Potássio/farmacologia , Segurança , Torsades de Pointes/fisiopatologiaRESUMO
BACKGROUND: Early diagnosis decreases the mortality of hepatocellular carcinoma (HCC). We aimed to investigate the usefulness of PIVKA-II, AFP, AFP-L3, CEA, and their combinations in the diagnosis of primary and metastatic HCC. METHODS: One hundred and twenty patients with primary HCC (PHC), 115 with metastatic HCC (MHC), 89 with chronic liver disease (CLD), and 116 healthy volunteers were included. The diagnostic values of each marker and their combinations for HCC diagnosis were represented by ROC curve analyses. RESULTS: PIVKA-II, AFP, and AFP-L3 levels in PHC group were higher than that in normal control, CLD, and MHC groups. CEA levels in MHC group were higher than that in the other three groups. When the four markers were analyzed individually, PIVKA-II showed the highest positive rate in PHC group (76.7%) and CEA showed the highest positive rate in MHC group (69.6%). PIVKA- II showed the largest area under ROC curve (AUC = 0.835) to discriminate PHC group from CLD group. Combined PIVKA-II with AFP-L3 increased the AUC to 0.910. CEA showed the highest AUC (0.849) to discriminate MHC group from CLD group. Combined CEA with PIVKA-II increased the AUC to 0.866. AFP-L3 alone showed the highest AUC (0.890) to discriminate MHC group from PHC group. Combined PIVKA-II with AFP-L3, and CEA increased the AUC to 0.957. CONCLUSION: PIVKA-II, AFP-L3, AFP, and CEA are effective biomarkers for the diagnosis of PHC and MHC. Their combinations could improve the diagnostic performance compared with each marker used alone in detecting PHC and MHC.
Assuntos
Biomarcadores Tumorais/sangue , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/patologia , Adulto , Idoso , Biomarcadores/sangue , Antígeno Carcinoembrionário/sangue , Estudos de Casos e Controles , Feminino , Humanos , Hepatopatias/sangue , Masculino , Pessoa de Meia-Idade , Precursores de Proteínas/sangue , ProtrombinaRESUMO
BACKGROUND: Scaffold proteins play a critical role in an increasing number of biological signaling processes, including simple tethering mechanism, regulating selectivity in pathways, shaping cellular behaviors. While many databases document the signaling pathways, few databases are devoted to the scaffold proteins that medicate signal transduction. RESULTS: Here, we have developed a user-friendly database, ScaPD, to describe computationally predicted, experimentally validated scaffold proteins and associated signaling pathways. It currently contains 273 scaffold proteins and 1118 associated signaling pathways. The database allows users to search, navigate and download the scaffold protein-mediated signaling networks. CONCLUSIONS: Manually curated and predicted scaffold protein data will be a foundation for further investigation of the scaffold protein in the signal transduction. With maintained up-to-date data, ScaPD ( http://bioinfo.wilmer.jhu.edu/ScaPD ) will be a valuable resource for understanding how individual signaling pathways are regulated.
Assuntos
Bases de Dados de Proteínas , Proteínas/metabolismo , Sequência de Aminoácidos , Ontologia Genética , Humanos , Domínios Proteicos , Proteínas/química , Transdução de Sinais , Estatística como AssuntoRESUMO
BACKGROUND AND AIM: Examination of top-cited articles is a tool that can help to identify and monitor outstanding scientific researches and landmark papers. We aimed to identify the 100 most cited published papers in peer-reviewed biomedical journals in the field of digestive diseases and to examine their characteristics. METHODS: The Web of Science (including Science Citation Index) was searched for the most cited papers related to digestive diseases, published from 1955 to the present. The top 100 most cited articles were identified. The number of citations, countries, and institutions of origin, year of publication, study design, topic, and levels of evidence of the articles were noted and analyzed. RESULTS: The most top-cited articles had a mean of 1375 citations. These articles were published between 1978 and 2009 in 29 high-impact journals, with the New England Journal of Medicine (n = 22) topping the list. Of the 100 articles, 34 were clinical studies, 15 were review articles, and 34 were concerned basic science. These articles came from 18 countries, with the USA contributing most of the top-cited articles (n = 53). Eighty-seven institutions produced these 100 top-cited articles, led by the University of Barcelona (n = 4). Seven persons authored two or more of these top-cited articles. The mostly represented specialty was gastrointestinal oncology (n = 49). CONCLUSIONS: Our study can give a historical perspective on the scientific progress of digestive diseases, as well as allow for recognition of most important advances in this area and provide useful information to guide future researches.
Assuntos
Bibliografia de Medicina , Doenças do Sistema Digestório , Gastroenterologia , Publicações Periódicas como Assunto/estatística & dados numéricos , Publicações Periódicas como Assunto/tendências , Medicina Baseada em Evidências , Gastroenterologia/tendências , Humanos , Internet , Revisão da Pesquisa por Pares , Projetos de Pesquisa , Espanha , Fatores de Tempo , Estados UnidosRESUMO
RATIONALE: Synthetic and natural coumarin derivatives possess a wide range of biological activities. Fragmentation pathway studies are important in identifying both naturally occurring coumarins and synthetic coumarins with novel structures and properties. METHODS: The fragmentation pathways of eleven coumarin derivatives are investigated by electrospray ionization (ESI) ion-trap mass spectrometry (ESI-ITMSn ) and ESI quadrupole time-of-flight mass spectrometry (QTOFMS) in positive mode. Compounds 1-9 in this study were newly synthesized in our laboratory. Compounds 10 and 11 were isolated from the root of Zanthoxylum armatum. RESULTS: The major fragmentation pathways for 11 coumarin derivatives are greatly affected by the heterocyclic ring structures and the side-chain substituents. Typical losses of small neutral molecules, such as CH3 CH2 OH, CH2 =CH2 , CO, and H2 O, are observed for compounds 1-5. Compounds 6-9 share similar fragmentation pathways through losses of CO, aromatic rings, and the coumarin skeleton. The main product ions at m/z 205, 219, and 220 observed for compounds 10 and 11 are produced by the loss of C5 H12 O2 , C4 H10 O2 , and the C4 H9 O2 radical, respectively. CONCLUSIONS: The fragmentation pathways of 11 coumarin derivatives are elucidated based on ITMSn and QTOFMS spectral data. Differences in the structures of the heterocyclic rings and side-chain substituents strongly affect the fragmentation pathways of the coumarins. The present results will facilitate further research into the fragmentation pathways and structural characterization of these classes of compounds with diverse structures. Copyright © 2015 John Wiley & Sons, Ltd.
RESUMO
BACKGROUND: Keloid is a benign hyperplastic dermatosis with high recurrence rate and complex pathogenesis. There is no universally effective treatment yet. New therapies and elucidation of pathogenesis are urgently required. AIMS: To explore the function of IRE1α/XBP1 in keloid fibroblasts and to investigate the potential mechanism of artesunate in inhibiting keloid hyperplasia. METHODS: Human keloid fibroblasts (KFs) were cultured, and the expressions of XBP1 and TGF-ß1 were detected by immunohistochemistry. The expression of IRE1 was interfered with through cell transfection and the effects of IRE1 interference on cell proliferation and the cell cycle were assessed using MTS, colony formation assays, and flow cytometry. Detection of the expressions of XBP1 and TGF-ß1 by qRT-PCR and Western blot. Then artesunate was applied to a subset of the cells, and its effects on cell viability and the expression of related proteins using the same methods. RESULTS: The IRE1α/XBP1 pathway was activated in KFs. Knocking out the gene IRE1α can inhibit the expression of TGF-ß1, in addition, the cell viability and cell cycle progression of KFs were also significantly affected. After artesunate treatment, there was a remarkable reduction in cell proliferation. Meanwhile, the cell cycle of KFs treated with artesunate was blocked in G1 phase.After upregulating the expression of IRE1α and treating KFs with artesunate, both cell cycle and proliferation showed inhibitory effects, and related proteins also exhibited suppressed expression. CONCLUSIONS: The IRE1α/XBP1 pathway is activated in keloid, and inhibiting the expression of this pathway can affect the cell proliferation activity. In addition, artesunate also has a significant effect on fibroblast proliferation, and the IRE1α/XBP1 pathway may participate in this process. These findings suggest that IRE1α/XBP1 signal pathway may be a potential target for scar treatment, and artesunate could also be a powerful candidate for keloid treatment.
Assuntos
Artemisininas , Artesunato , Proliferação de Células , Endorribonucleases , Fibroblastos , Queloide , Proteínas Serina-Treonina Quinases , Transdução de Sinais , Fator de Crescimento Transformador beta1 , Proteína 1 de Ligação a X-Box , Adulto , Feminino , Humanos , Masculino , Artemisininas/farmacologia , Artemisininas/uso terapêutico , Artesunato/farmacologia , Artesunato/uso terapêutico , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Endorribonucleases/metabolismo , Endorribonucleases/genética , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Queloide/metabolismo , Queloide/tratamento farmacológico , Queloide/patologia , Queloide/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo , Proteína 1 de Ligação a X-Box/metabolismo , Proteína 1 de Ligação a X-Box/genéticaRESUMO
Introduction: Soil physicochemical properties and nutrient composition play a significant role in shaping microbial communities, and facilitating soil phosphorus (P) transformation. However, studies on the mechanisms of interactions between P transformation characteristics and rhizosphere microbial diversity in P-deficient soils on longer time scales are still limited. Methods: In this study, rhizosphere soils were collected from a pure plantation of Parashorea chinensis (P. chinensis) at six stand ages in the subtropical China, and the dynamic transformation characteristics of microbial diversity and P fractions were analyzed to reveal the variation of their interactions with age. Results: Our findings revealed that the rhizosphere soils across stand ages were in a strongly acidic and P-deficient state, with pH values ranging from 3.4 to 4.6, and available P contents ranging from 2.6 to 7.9 mg·kg-1. The adsorption of P by Fe3+ and presence of high levels of steady-state organic P highly restricted the availability of P in soil. On long time scales, acid phosphatase activity and microbial biomass P were the main drivers of P activation. Moreover, pH, available P, and ammonium nitrogen were identified as key factors driving microbial community diversity. As stand age increased, most of the nutrient content indicators firstly increased and then decreased, the conversion of other forms of P to bio-available P became difficult, P availability and soil fertility began to decline. However, bacteria were still able to maintain stable species abundance and diversity. In contrast, stand age had a greater effect on the diversity of the fungal community than on the bacteria. The Shannon and Simpson indices varied by 4.81 and 0.70 for the fungi, respectively, compared to only 1.91 and 0.06 for the bacteria. Microorganisms play a dominant role in the development of their relationship with soil P. Discussion: In conclusion, rhizosphere microorganisms in P. chinensis plantations gradually adapt to the acidic, low P environment over time. This adaptation is conducive to maintaining P bioeffectiveness and alleviating P limitation.
RESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Mammary gland hyperplasia, a prevalent benign breast condition, often serves as a precursor to various other breast diseases. He-Zi-3 soup (HZ-3), a traditional Mongolian remedy, is utilized for treating this condition. AIM OF THE STUDY: To explore the effect and underlying mechanism of HZ-3, a Mongolian medicinal preparation, on mammary gland hyperplasia. MATERIALS AND METHODS: This study aimed to assess the impact of different doses of HZ-3 in a rat model of mammary hyperplasia. The active components within HZ-3 drug serum were identified and analyzed through network pharmacology and target prediction. To elucidate the underlying mechanism of HZ-3 in addressing mammary hyperplasia, we conducted a series of investigations on estradiol-induced mammary hyperplasia in model rates. Assessments included measurements of papilla width and height, hematoxylin and eosin staining, Masson staining, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), Western blot, and immunohistochemistry. RESULTS: Our investigation revealed the identification of 21 compounds, primarily terpenoids, through serum medicinal chemistry screening. Utilizing network pharmacological analysis, we observed predominant regulation through the estrogen pathway, closely associated with key genes including esr1,esr2, ncoa1, krt 19, ctsd, ebag 9, and bcl-2. Assessments encompassing nipple height and width, histological examination, immunohistochemical analysis, and serum hormone levels via enzyme-linked immunosorbent assay demonstrated the inhibitory effect of HZ-3 on mammary hyperplasia in rat models. RT-qPCR and Western blot analyses corroborated these findings, affirming the suppression of mammary hyperplasia by HZ-3 through the activation of estrogen pathway signaling.
Assuntos
Hiperplasia , Glândulas Mamárias Animais , Ratos Sprague-Dawley , Animais , Feminino , Hiperplasia/tratamento farmacológico , Glândulas Mamárias Animais/efeitos dos fármacos , Glândulas Mamárias Animais/patologia , Ratos , Estrogênios/farmacologia , Progestinas/farmacologia , Medicina Tradicional da Mongólia , Estradiol/sangue , Estradiol/farmacologia , Extratos Vegetais/farmacologiaRESUMO
Deep learning neural networks are often described as black boxes, as it is difficult to trace model outputs back to model inputs due to a lack of clarity over the internal mechanisms. This is even true for those neural networks designed to emulate mechanistic models, which simply learn a mapping between the inputs and outputs of mechanistic models, ignoring the underlying processes. Using a mechanistic model studying the pharmacological interaction between opioids and naloxone as a proof-of-concept example, we demonstrated that by reorganizing the neural networks' layers to mimic the structure of the mechanistic model, it is possible to achieve better training rates and prediction accuracy relative to the previously proposed black-box neural networks, while maintaining the interpretability of the mechanistic simulations. Our framework can be used to emulate mechanistic models in a large parameter space and offers an example on the utility of increasing the interpretability of deep learning networks.
Assuntos
Aprendizado Profundo , Naloxona , Redes Neurais de Computação , Biologia de Sistemas , Biologia de Sistemas/métodos , Naloxona/farmacologia , Humanos , Farmacologia/métodos , Analgésicos Opioides/farmacologia , Simulação por ComputadorRESUMO
Despite a rapid increase in pediatric mortality rate from prescription and illicit opioids, there is limited research on the dose-dependent impact of opioids on respiratory depression in children, the leading cause of opioid-associated death. In this article, we extend a previously developed translational model to cover pediatric populations by incorporating age-dependent pharmacokinetic, pharmacodynamic, and physiological changes compared to adults. Our model reproduced previous perioperative clinical findings that adults and children have similar risk of respiratory depression at the same plasma fentanyl concentration when specific endpoints (minute ventilation, CO2 tension in the blood) were used. However, our model points to a potential caveat that, in a perioperative setting, routine use of mechanical ventilation and supplemental oxygen maintained the blood and tissue oxygen partial pressures in patients and prevented the use of oxygen-related endpoints to evaluate the consequences of respiratory depression. In a community setting when such oxygenation procedures are not immediately available, our model suggests that the higher oxygen demand and reduced cerebrovascular reactivity could make children more susceptible to severe hypoxemia and brain hypoxia, even with the same plasma fentanyl concentration as adults. Our work indicates that when developing intervention strategies to protect children from opioid overdose in a community setting, these pediatric-specific factors may need to be considered.
Assuntos
Overdose de Opiáceos , Insuficiência Respiratória , Adulto , Humanos , Criança , Insuficiência Respiratória/induzido quimicamente , Oxigênio , Analgésicos Opioides/efeitos adversos , Fentanila/efeitos adversosRESUMO
Antibiotics used systemically to treat infections may have off-target effects on the gut microbiome, potentially resulting in the emergence of drug-resistant bacteria or selection of pathogenic species. These organisms may present a risk to the host and spread to the environment with a risk of transmission in the community. To investigate the risk of emergent antibiotic resistance in the gut microbiome following systemic treatment with antibiotics, this metagenomic analysis project used next-generation sequencing, a custom-built metagenomics pipeline, and differential abundance analysis to study the effect of antibiotics (ampicillin, ciprofloxacin, and fosfomycin) in monotherapy and different combinations at high and low doses, to determine the effect on resistome and taxonomic composition in the gut of Balb/c mice. The results showed that low-dose monotherapy treatments showed little change in microbiome composition but did show an increase in expression of many antibiotic-resistant genes (ARGs) posttreatment. Dual combination treatments allowed the emergence of some conditionally pathogenic bacteria and some increase in the abundance of ARGs despite a general decrease in microbiota diversity. Triple combination treatment was the most successful in inhibiting emergence of relevant opportunistic pathogens and completely suppressed all ARGs after 72 h of treatment. The relative abundances of mobile genetic elements that can enhance transmission of antibiotic resistance either decreased or remained the same for combination therapy while increasing for low-dose monotherapy. Combination therapy prevented the emergence of ARGs and decreased bacterial diversity, while low-dose monotherapy treatment increased ARGs and did not greatly change bacterial diversity.
Assuntos
Microbioma Gastrointestinal , Microbiota , Animais , Camundongos , Antibacterianos/farmacologia , Ampicilina/farmacologia , Ciprofloxacina/farmacologia , Bactérias/genética , Genes BacterianosRESUMO
The pathogenesis of antibodies in severe alcoholic hepatitis (SAH) remains unknown. We sought to determine if there was antibody deposition in SAH livers and whether antibodies extracted from SAH livers were cross-reactive against both bacterial antigens and human proteins. We analyzed immunoglobulins (Ig) in explanted livers from SAH patients (n=45) undergoing liver transplantation and tissue from corresponding healthy donors (HD, n=10) and found massive deposition of IgG and IgA isotype antibodies associated with complement fragment C3d and C4d staining in ballooned hepatocytes in SAH livers. Ig extracted from SAH livers, but not patient serum exhibited hepatocyte killing efficacy in an antibody-dependent cell-mediated cytotoxicity (ADCC) assay. Employing human proteome arrays, we profiled the antibodies extracted from explanted SAH, alcoholic cirrhosis (AC), nonalcoholic steatohepatitis (NASH), primary biliary cholangitis (PBC), autoimmune hepatitis (AIH), hepatitis B virus (HBV), hepatitis C virus (HCV) and HD livers and found that antibodies of IgG and IgA isotypes were highly accumulated in SAH and recognized a unique set of human proteins as autoantigens. The use of an E. coli K12 proteome array revealed the presence of unique anti- E. coli antibodies in SAH, AC or PBC livers. Further, both Ig and E. coli captured Ig from SAH livers recognized common autoantigens enriched in several cellular components including cytosol and cytoplasm (IgG and IgA), nucleus, mitochondrion and focal adhesion (IgG). Except IgM from PBC livers, no common autoantigen was recognized by Ig and E. coli captured Ig from AC, HBV, HCV, NASH or AIH suggesting no cross-reacting anti- E. coli autoantibodies. The presence of cross-reacting anti-bacterial IgG and IgA autoantibodies in the liver may participate in the pathogenesis of SAH.
RESUMO
The pathogenesis of antibodies in severe alcoholic hepatitis (SAH) remains unknown. We analyzed immunoglobulins (Ig) in explanted livers from SAH patients (n=45) undergoing liver transplantation and tissues from corresponding healthy donors (HD, n=10) and found massive deposition of IgG and IgA isotype antibodies associated with complement fragment C3d and C4d staining in ballooned hepatocytes in SAH livers. Ig extracted from SAH livers, but not patient serum exhibited hepatocyte killing efficacy. Employing human and Escherichia coli K12 proteome arrays, we profiled the antibodies extracted from explanted SAH, livers with other diseases, and HD livers. Compared with their counterparts extracted from livers with other diseases and HD, antibodies of IgG and IgA isotypes were highly accumulated in SAH and recognized a unique set of human proteins and E. coli antigens. Further, both Ig- and E. coli-captured Ig from SAH livers recognized common autoantigens enriched in several cellular components including cytosol and cytoplasm (IgG and IgA), nucleus, mitochondrion, and focal adhesion (IgG). Except IgM from primary biliary cholangitis livers, no common autoantigen was recognized by Ig- and E. coli-captured Ig from livers with other diseases. These findings demonstrate the presence of cross-reacting anti-bacterial IgG and IgA autoantibodies in SAH livers.
Assuntos
Hepatite Alcoólica , Humanos , Escherichia coli , Imunoglobulina A , Autoanticorpos , Imunoglobulina G , Imunoglobulina MRESUMO
Bullous pemphigoid (BP) patients were vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection because they have similar risk factors, so we should pay attention to patients with BP during the epidemic of coronavirus disease-19 (COVID-19). As far as treatment is concerned, many strategies for BP were changed during the epidemic. Plasmapheresis not only has been included in the guidelines for BP but also has been used successfully to rescue COVID-19 patients, especially in severe cases. Therefore, it is a feasible choice for BP patients, especially for refractory BP patients, infected with SARS-CoV-2. Apart from these, we have reviewed some points for attention during the plasmapheresis session.