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1.
BMC Cancer ; 23(1): 674, 2023 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-37464398

RESUMO

BACKGROUND: Annexins are a family of proteins involved in a wide variety of cellular processes such as inflammation, proliferation, differentiation, apoptosis, migration and membrane repair. However, the role of most Annexins in renal cell carcinoma (RCC) remained unclear. METHODS: The differentially expressed Annexins in RCC compared with normal controls were screened applying the TCGA database. The correlation of differentially expressed Annexins with clinical stages, grades and overall survival was analyzed to explore the clinical significance of Annexins in RCC. Then ANXA8 was selected and further stained in the discover and validation RCC cohort. The correlation of ANXA8 expression with clinical parameter was verified at the protein level. To explore the potential function of ANXA8, ANXA8 was knockdown in the RCC cell line and further analyzed using transcriptome and bioinformatic analysis. RESULTS: mRNA expression of ANXA1, ANXA2R, ANXA4, ANXA8, ANXA8L1 and ANXA13 were significantly upregulated in RCC compared with normal kidney tissues. In contrast, ANXA3 and ANXA9 mRNA expression was significantly downregulated. Higher expression of ANXA2R, ANXA8 and ANXA8L1 were correlated with worse overall survival, while lower expression of ANXA3, ANXA9 and ANXA13 were associated with worse clinical outcomes in RCC patients. We further demonstrated that ANXA8 expression was significantly increased in RCC compared with normal renal tissues at the protein level. And higher protein expression of ANXA8 was associated with higher clinical grades. Through the bioinformatics analysis and cell cycle analysis, we found knockdown of ANXA8 mainly influenced the cell cycle and DNA replication. The top ten hub genes consist of CDC6, CDK2, CHEK1, CCNB1, ORC1, CHEK2, MCM7, CDK1, PCNA and MCM3. CONCLUSIONS: Multiple members of Annexins were abnormally expressed and associated with the prognosis of RCC. The expression of ANXA8 was significantly increased in RCC and associated with poor prognosis. ANXA8 might influence the cell cycle and could be a potential biomarker and therapeutic target for RCC.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Humanos , Anexinas/genética , Anexinas/metabolismo , Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Prognóstico , RNA Mensageiro/genética
2.
Bioorg Med Chem Lett ; 73: 128884, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-35835377

RESUMO

11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) has been identified as the primary enzyme responsible for the activation of hepatic cortisone to cortisol in specific peripheral tissues, resulting in the concomitant antagonism of insulin action within these tissues. Dysregulation of 11ß-HSD1, particularly in adipose tissues, has been associated with a variety of ailments including metabolic syndrome and type 2 diabetes mellitus. Therefore, inhibition of 11ß-HSD1 with a small nonsteroidal molecule is therapeutically desirable. Implementation of a scaffold-hopping approach revealed a 3-point pharmacophore for 11ß-HSD1 that was utilized to design a 2-spiroproline derivative as a steroid mimetic scaffold. Reiterative optimization provided valuable insight into the bioactive conformation of our novel scaffold and led to the discovery of several leads, such as compounds 39 and 51. Importantly, deleterious hERG inhibition and pregnane X receptor induction were mitigated by the introduction of a 4-hydroxyl group to the proline ring system.


Assuntos
Diabetes Mellitus Tipo 2 , Síndrome Metabólica , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Hidrocortisona/metabolismo
3.
Bioorg Med Chem Lett ; 69: 128782, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35537608

RESUMO

11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) has been identified as the primary enzyme responsible for the activation of hepatic cortisone to cortisol in specific peripheral tissues resulting in the concomitant antagonism of insulin action within these tissues. Dysregulation of 11ß-HSD1, particularly in adipose tissues, has been associated with metabolic syndrome and type 2 diabetes mellitus. Therefore, inhibition of 11ß-HSD1 with a small nonsteroidal molecule is therapeutically desirable. Implementation of a scaffold-hopping approach revealed a three-point pharmacophore for 11ß-HSD1 that was utilized to design a steroid mimetic scaffold. Reiterative optimization provided valuable insight into the bioactive conformation of our novel scaffold and led to the discovery of INCB13739. Clinical evaluation of INCB13739 confirmed for the first time that tissue-specific inhibition of 11ß-HSD1 in patients with type 2 diabetes mellitus was efficacious in controlling glucose levels and reducing cardiovascular risk factors.


Assuntos
Diabetes Mellitus Tipo 2 , Síndrome Metabólica , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Hidrocortisona/metabolismo , Síndrome Metabólica/metabolismo
4.
Zhonghua Nan Ke Xue ; 27(4): 319-323, 2021 Apr.
Artigo em Zh | MEDLINE | ID: mdl-34914214

RESUMO

OBJECTIVE: To explore the application value of preputial endoscopy in the treatment of phimosis. METHODS: The clinical data were obtained on 58 cases of phimosis with an obvious narrow ring at the prepuce mouth and unable to reveal the glans penis when pushed up, which were treated in hour department from October 2018 to May 2020. The patients underwent preputial endoscopic examination followed by circumcision (group A, n = 30) or simple circumcision (group B, n = 28). A ureteroscope was used for preputial endoscopy, and the foreign matter removed with forceps to prepare for later circumcision. Under surface anesthesia, the ureteroscope was entered into the preputial cavity to observe the intactness and smoothness of the right, left and anterior walls and the frenulum side, as well as possible bleeding, tumor or hypospadias. RESULTS: Preputial endoscopy was successfully performed in all the 30 cases, which revealed 1 case of adhesive integration of the inner preputial lamina to the glans, 1 case of hypospadias, 2 cases of preputial adhesion and 2 cases of glans hemorrhage. Pathological biopsy confirmed penile cancer in 1 of the 6 cases. Lateral wall hemorrhage was found in 4 cases, preputial stones in 3, which was removed with foreign matter forceps, and preputial infection in 5 cases, which was treated by intrapreputial irrigation and antibiotic anti-inflammation therapy. The preputial endoscopic examinations lasted (6.52 ± 2.03) min. The operation time was significantly shorter in group A than in B (ï¼»37.81 ± 4.09ï¼½ vs ï¼»48.04 ± 5.48ï¼½ min, P < 0.01), and so were the postoperative pain duration (ï¼»110.74 ± 22.09ï¼½ vs ï¼»121.43 ± 26.80ï¼½ min, P < 0.01) and postoperative recovery time (ï¼»7.96 ± 1.83ï¼½ vs ï¼»12.04 ± 3.28ï¼½ d, P < 0.01). CONCLUSIONS: Preputial endoscopy is a safe and efficient method for the diagnosis and treatment of phimosis, with the advantages of simple operation, short examination time and less intraoperative pain, making essential preparations for subsequent circumcision.


Assuntos
Circuncisão Masculina , Hipospadia , Fimose , Endoscopia , Prepúcio do Pênis/cirurgia , Humanos , Masculino , Fimose/cirurgia
5.
J Pharmacol Exp Ther ; 374(1): 211-222, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32345620

RESUMO

The clinical use of first-generation phosphoinositide 3-kinase (PI3K)δ inhibitors in B-cell malignancies is hampered by hepatotoxicity, requiring dose reduction, treatment interruption, and/or discontinuation of therapy. In addition, potential molecular mechanisms by which resistance to this class of drugs occurs have not been investigated. Parsaclisib (INCB050465) is a potent and selective next-generation PI3Kδ inhibitor that differs in structure from first-generation PI3Kδ inhibitors and has shown encouraging anti-B-cell tumor activity and reduced hepatotoxicity in phase 1/2 clinical studies. Here, we present preclinical data demonstrating parsaclisib as a potent inhibitor of PI3Kδ with over 1000-fold selectivity against other class 1 PI3K isozymes. Parsaclisib directly blocks PI3K signaling-mediated cell proliferation in B-cell lines in vitro and in vivo and indirectly controls tumor growth by lessening immunosuppression through regulatory T-cell inhibition in a syngeneic lymphoma model. Diffuse large B-cell lymphoma cell lines overexpressing MYC were insensitive to proliferation blockade via PI3Kδ signaling inhibition by parsaclisib, but their proliferative activities were reduced by suppression of MYC gene transcription. Molecular structure analysis of the first- and next-generation PI3Kδ inhibitors combined with clinical observation suggests that hepatotoxicity seen with the first-generation inhibitors could result from a structure-related off-target effect. Parsaclisib is currently being evaluated in multiple phase 2 clinical trials as a therapy against various hematologic malignancies of B-cell origin (NCT03126019, NCT02998476, NCT03235544, NCT03144674, and NCT02018861). SIGNIFICANCE STATEMENT: The preclinical properties described here provide the mechanism of action and support clinical investigations of parsaclisib as a therapy for B-cell malignancies. MYC overexpression was identified as a resistance mechanism to parsaclisib in DLBCL cells, which may be useful in guiding further translational studies for the selection of patients with DLBCL who might benefit from PI3Kδ inhibitor treatment in future trials. Hepatotoxicity associated with first-generation PI3Kδ inhibitors may be an off-target effect of that class of compounds.


Assuntos
Fígado/efeitos dos fármacos , Linfoma/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/efeitos adversos , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Pirazóis/efeitos adversos , Pirazóis/farmacologia , Pirimidinas/efeitos adversos , Pirimidinas/farmacologia , Pirrolidinas/efeitos adversos , Pirrolidinas/farmacologia , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/farmacologia , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Rev Cardiovasc Med ; 21(4): 635-641, 2020 12 30.
Artigo em Inglês | MEDLINE | ID: mdl-33388009

RESUMO

To investigate the right heart function in coronavirus disease 2019 (COVID-19) patients with acute respiratory distress syndrome (ARDS), a retrospective analysis of 49 COVID-19 patients with ARDS was performed. Patients were divided into severe group and critically-severe group according to the severity of illness. Age-matched healthy volunteers were recruited as a control group. The cardiac cavity diameters, tricuspid annular plane systolic excursion (TAPSE), tricuspid valve regurgitation pressure gradient biggest (TRPG), pulmonary arterial systolic pressure (PASP), maximum inferior vena cava diameter (IVCmax) and minimum diameter (IVCmin), and inferior vena cava collapse index (ICV-CI) were measured using echocardiography. We found that the TAPSE was significantly decreased in pneumonia patients compared to healthy subjects (P < 0.0001), and it was significantly lower in critically-severe patients (P = 0.0068). The TAPSE was less than 17 mm in three (8.6%) severe and five (35.7%) critically-severe patients. In addition, the TAPSE was significantly decreased in severe ARDS patients than in mild ARDS patients. The IVCmax and IVCmin were significantly increased in critically-severe patients compared to healthy subjects and severe patients (P < 0.01), whereas the ICV-CI was significantly decreased (P < 0.05). COVID-19 patients had significantly larger right atrium and ventricle than healthy controls (P < 0.01). The left ventricular ejection fraction (LVEF) in critically-severe patients was significantly lower than that in severe patients and healthy controls (P < 0.05). Right ventricular function was impaired in critically-severe COVID-19 patients. The assessment and protection of the right heart function in COVID-19 patients should be strengthened.


Assuntos
COVID-19/complicações , Ventrículos do Coração/fisiopatologia , Pandemias , Disfunção Ventricular Direita/etiologia , Função Ventricular Direita/fisiologia , COVID-19/epidemiologia , Ecocardiografia Doppler , Feminino , Seguimentos , Ventrículos do Coração/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Disfunção Ventricular Direita/diagnóstico , Disfunção Ventricular Direita/fisiopatologia
7.
Biosci Biotechnol Biochem ; 83(6): 1035-1044, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30973065

RESUMO

Pituitary adenomas (PA) are commonly occurring benign neoplasms. Identification of molecular pathway resulting in pituitary tumorigenesis remains challenges in endocrine oncology. The present study was conducted with aim of investigating the role of microRNA-543 (miR-543) in PA development. Up-regulated miR-543 and downregulated Smad7 were observed in PA tissues. Afterwards, the specific mechanism of miR-543 and Smad7 in PA were determined with the use of ectopic expression, depletion and reporter assay experiments. Smad7 was confirmed as a target gene of miR-543. HP75 cells treated with overexpressed miR-543 exhibited increased cell proliferation, migration and invasion, while decreased cell apoptosis as well as expression of Cleaved caspase-3 and Cleaved caspase-8 were observed. Suppression of miR-543 contributed to an opposite trend to the above findings. Based on the findings, the inhibition of miR-543 was found to play a tumor suppressive role in PA through the down-regulation of Wnt/ß-catenin pathway by negatively regulating Smad7.


Assuntos
Adenoma/metabolismo , Adenoma/patologia , Apoptose/genética , MicroRNAs/fisiologia , Invasividade Neoplásica/genética , Neoplasias Hipofisárias/metabolismo , Neoplasias Hipofisárias/patologia , Proteína Smad7/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismo , Adulto , Caspase 3/metabolismo , Caspase 8/metabolismo , Linhagem Celular , Movimento Celular/genética , Proliferação de Células/genética , Regulação para Baixo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Regulação para Cima
8.
J Pharmacol Exp Ther ; 364(1): 120-130, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29127109

RESUMO

Phosphatidylinositol 3-kinase delta (PI3Kδ) is a critical signaling molecule in B cells and is considered a target for development of therapies against various B cell malignancies. INCB040093 is a novel PI3Kδ small-molecule inhibitor and has demonstrated promising efficacy in patients with Hodgkin's lymphoma in clinical studies. In this study, we disclose the chemical structure and the preclinical activity of the compound. In biochemical assays, INCB040093 potently inhibits the PI3Kδ kinase, with 74- to >900-fold selectivity against other PI3K family members. In vitro and ex vivo studies using primary B cells, cell lines from B cell malignancies, and human whole blood show that INCB040093 inhibits PI3Kδ-mediated functions, including cell signaling and proliferation. INCB040093 has no significant effect on the growth of nonlymphoid cell lines and was less potent in assays that measure human T and natural killer cell proliferation and neutrophil and monocyte functions, suggesting that the impact of INCB040093 on the human immune system will likely be restricted to B cells. INCB040093 inhibits the production of macrophage-inflammatory protein-1ß (MIP-1beta) and tumor necrosis factor-ß (TNF-beta) from a B cell line, suggesting a potential effect on the tumor microenvironment. In vivo, INCB040093 demonstrates single-agent activity in inhibiting tumor growth and potentiates the antitumor growth effect of the clinically relevant chemotherapeutic agent, bendamustine, in the Pfeiffer cell xenograft model of non-Hodgkin's lymphoma. INCB040093 has a favorable exposure profile in rats and an acceptable safety margin in rats and dogs. Taken together, data presented in this report support the potential utility of orally administered INCB040093 in the treatment of B cell malignancies.


Assuntos
Antineoplásicos/farmacologia , Linfoma não Hodgkin/tratamento farmacológico , Neoplasias/tratamento farmacológico , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Animais , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Quimiocina CCL4/metabolismo , Cães , Feminino , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/metabolismo , Linfoma não Hodgkin/metabolismo , Masculino , Camundongos , Camundongos SCID , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Neoplasias/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Ratos , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo
9.
Neurourol Urodyn ; 37(4): 1272-1280, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29160569

RESUMO

AIMS: To investigate the feasibility of restoring bladder function and prevention of renal deterioration by neurorrhaphy in rats with neurogenic bladder (NB). METHODS: Forty-two rats were assigned to the end-to-side nerve coaptation group (ECG, n = 16), no nerve coaptation group (NCG, n = 16), and control group (CG, n = 10). In the ECG, the left ventral root (VR) and dorsal root (DR) of L6 and S1 were transected, and the distal stump of L6VR was sutured to the lateral face of L4VR. In the NCG, the left VR and DR of L6 and S1 were transected, but coaptation was not performed. In the CG, no operation was performed. Nerve regeneration, bladder function, and renal function were evaluated by FluoroGold (FG) retrograde tract tracing, cystometry, electrical stimulation, MRI, histology and biochemical assays. RESULTS: In the ECG, FG-labeled neurons were observed in the left ventral horn of L4 spinal cord. There was a significant increase in intravesical pressure upon stimulation of the left L4VR proximal to the coaptation. Maximum cystometric capacity, post-void residual urine, bladder compliance and weight, serum creatinine, blood urea nitrogen, and fibrotic area of bladder and kidney were lower in the ECG than in the NCG, but higher than the CG. Hydronephrosis was noticed in ECG and NCG rats. Maximum detrusor voiding pressure was higher in the ECG and CG than in the NCG. CONCLUSIONS: End-to-side neurorrhaphy is a useful method for restoring bladder function and preventing renal injury in rats with NB.


Assuntos
Rim/fisiopatologia , Regeneração Nervosa , Procedimentos de Cirurgia Plástica/métodos , Raízes Nervosas Espinhais/fisiopatologia , Bexiga Urinaria Neurogênica/cirurgia , Animais , Masculino , Ratos , Ratos Sprague-Dawley , Traumatismos da Medula Espinal/fisiopatologia , Bexiga Urinaria Neurogênica/fisiopatologia , Micção/fisiologia
10.
Acta Paediatr ; 103(10): e450-3, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24912545

RESUMO

AIM: The neonatal period is critical in bladder development, encompassing the transition from foetal bladder contractions to voluntary infant urination. The aim of this study was to investigate different voiding parameters between male and female newborn infants. METHODS: We studied 102 healthy, single birth newborn infants - 54 preterm and 48 full-term - without lower urinary tract diseases, hospitalised in the neonatal intensive care unit from March 2011 to March 2012. Free voiding was observed from 9 a.m. to 9 p.m., and the free voiding parameters and fluid intake were recorded and compared between male and female newborn infants using the Student's t-test and chi-square test. RESULTS: Male preterm newborns demonstrated larger mean postvoid residual volumes and lower bladder emptying rates than female preterm newborns (p < 0.05), and male full-term newborns had lower bladder emptying rates than female full-term newborns (p < 0.05). The bladder emptying rates of newborns defecating simultaneously with voiding were not statistically different between males and females of the same gestational age (p > 0.05). CONCLUSION: Male newborns were more likely to have larger postvoid residual volumes than females, and defecating simultaneously with voiding may promote bladder emptying in male newborns.


Assuntos
Recém-Nascido/fisiologia , Caracteres Sexuais , Micção , Feminino , Humanos , Recém-Nascido Prematuro/fisiologia , Masculino
11.
J Pain Res ; 16: 2543-2552, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37521009

RESUMO

Background: Intravenous labor analgesia is recommended as an alternative for parturients who have contraindications to epidural analgesia. There are several opioid analgesics and different administering regimens used in the clinic. This study aimed to compare the effectiveness and safety of two intravenous remifentanil dosage regimens in the first labor stage. Patients and Methods: One hundred and fifteen parturients with a contraindication to epidural analgesia but were willing to receive systemic labor analgesia were randomized into group A received a fixed dose of remifentanil throughout the first stage of labor, and group B received an elevated dose of remifentanil during the active phase of the first stage both by patient-controlled analgesia (PCA). Maternal numerical rating scale (NRS) pain score and oxygen desaturation, sedation efficacy, satisfaction, as well as maternal and fetal adverse reactions were recorded and compared. Results: The mean NRS pain scores before analgesia and in the latent phase showed no statistically significant difference between the two groups (P > 0.05). However, during the active phase, group B demonstrated significantly lower mean NRS pain scores and lowest pain score compared to group A (P < 0.05). Furthermore, group B exhibited higher overall sedation scores and satisfaction scores in comparison to group A (P < 0.05). The incidence of adverse reactions between the two groups was similar (P > 0.05). Conclusion: Relatively elevated intravenous dosage of remifentanil with PCA during the active phase in the first stage of labor is safe and more effective than a fixed-dosage regimen for labor analgesia. Trial Registration: This study was registered with ChiCTR on 24/08/2021 with trial identification number: ChiCTR2100050247. First participant was recruited on 31/08/2021. The last patient was recruited on 12/08/2022.

12.
Biochim Biophys Acta Rev Cancer ; 1877(3): 188723, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35314212

RESUMO

Tumor suppressor activation or reactivation has long been a sought-after, yet elusive, therapeutic strategy for human cancer. Phosphatase and tensin homolog (PTEN) is one of the most frequently mutated tumor suppressor genes that regulate many biological processes, including proliferation, survival, cellular architecture, motility, energy metabolism, and genomic stability. As a dose-dependent tumor suppressor, subtle reductions in PTEN protein levels and activity will alter the gene-expression profiles involved in tumor progression, laying the foundation for PTEN reactivation in cancer treatment. However, treatment strategies that manipulate and/or replace PTEN activity to successfully block and reverse the destructive progression of cancer are not yet available. Ubiquitination/de-ubiquitination is one of the major regulatory mechanisms of PTEN by influencing its stability, subcellular localization, and activity. Recent discoveries, including new ubiquitination sites, E3 ubiquitin ligases, de-ubiquitinases of PTEN, and participation of accessory and adaptor proteins, have revealed new modes of PTEN ubiquitination regulation. Furthermore, either pharmaceutical or gene-targeted inhibition of E3 ligase-mediated ubiquitination of PTEN potently releases PTEN's anticancer activity and suppresses tumorigenesis. These findings shed light on therapeutic strategies for reactivating PTEN in cancer that target ubiquitination/de-ubiquitination. Therefore, a comprehensive understanding of the ubiquitination/de-ubiquitination regulation of PTEN could help improve clinical conceptualization and treatment of cancer. This review aimed to summarize and discuss recent discoveries on PTEN ubiquitination and de-ubiquitination, with the goal of providing a systematic summary in the field and promoting clinical transformation of targeting ubiquitination for PTEN reactivation in the treatment of cancer.


Assuntos
Neoplasias , PTEN Fosfo-Hidrolase , Ubiquitinação , Carcinogênese , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Neoplasias/genética , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
13.
World J Gastroenterol ; 28(19): 2123-2136, 2022 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-35664037

RESUMO

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a major cause of death in patients with severe acute pancreatitis (SAP). Although a series of prediction models have been developed for early identification of such patients, the majority are complicated or lack validation. A simpler and more credible model is required for clinical practice. AIM: To develop and validate a predictive model for SAP related ARDS. METHODS: Patients diagnosed with AP from four hospitals located at different regions of China were retrospectively grouped into derivation and validation cohorts. Statistically significant variables were identified using the least absolute shrinkage and selection operator regression method. Predictive models with nomograms were further built using multiple logistic regression analysis with these picked predictors. The discriminatory power of new models was compared with some common models. The performance of calibration ability and clinical utility of the predictive models were evaluated. RESULTS: Out of 597 patients with AP, 139 were diagnosed with SAP (80 in derivation cohort and 59 in validation cohort) and 99 with ARDS (62 in derivation cohort and 37 in validation cohort). Four identical variables were identified as independent risk factors for both SAP and ARDS: heart rate [odds ratio (OR) = 1.05; 95%CI: 1.04-1.07; P < 0.001; OR = 1.05, 95%CI: 1.03-1.07, P < 0.001], respiratory rate (OR = 1.08, 95%CI: 1.0-1.17, P = 0.047; OR = 1.10, 95%CI: 1.02-1.19, P = 0.014), serum calcium concentration (OR = 0.26, 95%CI: 0.09-0.73, P = 0.011; OR = 0.17, 95%CI: 0.06-0.48, P = 0.001) and blood urea nitrogen (OR = 1.15, 95%CI: 1.09-1.23, P < 0.001; OR = 1.12, 95%CI: 1.05-1.19, P < 0.001). The area under receiver operating characteristic curve was 0.879 (95%CI: 0.830-0.928) and 0.898 (95%CI: 0.848-0.949) for SAP prediction in derivation and validation cohorts, respectively. This value was 0.892 (95%CI: 0.843-0.941) and 0.833 (95%CI: 0.754-0.912) for ARDS prediction, respectively. The discriminatory power of our models was improved compared with that of other widely used models and the calibration ability and clinical utility of the prediction models performed adequately. CONCLUSION: The present study constructed and validated a simple and accurate predictive model for SAP-related ARDS in patients with AP.


Assuntos
Pancreatite , Síndrome do Desconforto Respiratório , Doença Aguda , Humanos , Pancreatite/complicações , Pancreatite/diagnóstico , Curva ROC , Síndrome do Desconforto Respiratório/diagnóstico , Síndrome do Desconforto Respiratório/etiologia , Estudos Retrospectivos
14.
Acta Crystallogr Sect E Struct Rep Online ; 67(Pt 6): o1420, 2011 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-21754801

RESUMO

In the title compound, C(18)H(16)N(2)O(2)·H(2)O, the dihedral angle between the quinoline ring system and the benzene ring is 87.19 (8)°. In the crystal, water mol-ecules are linked to acetamide mol-ecules via inter-molecular O-H⋯N and O-H⋯O hydrogen bonds.

15.
J Int Med Res ; 49(5): 3000605211016623, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34038212

RESUMO

OBJECTIVE: Ultraviolet light-emitting diode (UV LED) irradiation at 280 nm has been confirmed to induce apoptosis in cultured HL-60 cells, but the underlying mechanisms remain unclear. This study aimed to investigate the effects of 280 nm UV LED irradiation on reactive oxygen species (ROS) production and mitochondrial membrane potential (MMP) in HL-60 cells. METHODS: HL-60 cells were irradiated with 0, 8, 15, or 30 J/m2 of 280 nm UV LED and incubated for 2 hours. The intracellular ROS levels were assessed using the fluorescent probe 2'-7'-dichlorodihydrofluorescein diacetate (DCFH-DA) and a fluorescence plate reader. MMP was determined by flow cytometry using 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazol-carbocyanine iodide (JC-1) staining. The apoptosis-related proteins Bax and Bcl-2 were evaluated by western blot. RESULTS: UV LED irradiation at 280 nm induced a dose-dependent increase in ROS production and loss of MMP, and it activated apoptosis at irradiation doses of 8 to 30 J/m2. These results were consistent with a previous apoptosis study from the authors' group. CONCLUSION: Enhanced ROS production and mitochondrial depolarization are two distinct but interacting events, and both are involved in UV LED-induced apoptosis in HL-60 cells.


Assuntos
Apoptose , Raios Ultravioleta , Células HL-60 , Humanos , Potencial da Membrana Mitocondrial , Espécies Reativas de Oxigênio
16.
World J Clin Cases ; 9(11): 2595-2601, 2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33889625

RESUMO

BACKGROUND: Currently, open reduction internal fixation is the conventional surgical method for treatment of double ulna and radius fracture. However, open reduction is associated with a high risk of complications. This case of forearm double fracture involved a patient treated using an Acumed intramedullary nail. The patient experienced good follow-up outcomes. The Acumed forearm intramedullary nail enables early functional exercise and hastens healing of the fracture. Few studies have reported on the use of this approach for the treatment of fractures. CASE SUMMARY: A 23-year-old male patient was admitted to hospital after 5 h of pain, swelling, and limited activity of left forearm caused by a careless fall. Physical examination showed stable basic vital signs, swelling of the left forearm, and severe pain when pressing on the injured part of the forearm. Further, friction was felt at the broken end of the bone; the skin was not punctured. Movement of the left hand was normal, and the left radial artery pulse was normal. Three-dimensional computed tomography examination showed an ulna fracture of the left forearm and comminuted fracture of the radius. The fracture was located in the upper third of the radius, with significant displacement on the fracture side. Clinical diagnosis further confirmed the left radius comminuted fracture and ulna fracture. After analyzing the fracture pattern, age, and other patient characteristics, we chose an Acumed nail for treatment and achieved good follow-up outcomes. CONCLUSION: Acumed forearm intramedullary nail for fixation of ulna and radius fracture reduced complication risk and resulted in good follow-up outcomes.

17.
Yi Chuan ; 32(12): 1256-62, 2010 Dec.
Artigo em Zh | MEDLINE | ID: mdl-21513151

RESUMO

The polymorphism of Interleukin-8 (IL8) gene were investigated for 610 Chinese Holstein cows of 30 bull families from a dairy farm in Shanghai using Polymerase Chain Reaction-Single Strand Conformation Polymorphism (PCR-SSCP) technique with a mixed animal model to verify the effects of the polymorphisms on some milk productive performance, tested day milk yield, tested day fat percentage, tested day milk protein percentage, 305 d corrected milk yield, 305 d milk fat yield, 305 d milk protein yield, and somatic cell score (SCS). The aim was to explore the significant molecular marker in practical dairy production. Three genotypes were identified and the genotypic frequencies of KK, KA, and AA were 0.187, 0.451, and 0.362, respectively. The gene frequencies of K and A were 0.412 and 0.588. The results showed highly significant (P < 0.01) association of IL8 mutations with tested day milk yield, 305 d milk protein yield, 305 d corrected milk yield and 305 d milk fat yield, SCS and tested day milk protein percentage (P < 0.05). However, no association (P > 0.05) with tested day milk fat percentage was recorded. The cows with KK genotype had higher tested day milk yield, 305 d milk protein yield, 305 d corrected milk yield and 305 d milk fat yield than those with AA and KA genotypes (P < 0.01). The least square mean of SCS for KK was significantly lower than that with AA and KA genotypes (P < 0.01). AA genotype was significant lower in tested day milk protein percentage than KK and KA genotypes (P < 0.05). The IL8 gene genetic diversity has a great genetic effect on milk traits and mastitis resistance and could be a useful genetic marker for Chinese Holstein breeding.


Assuntos
Bovinos/genética , Bovinos/fisiologia , Interleucina-8/genética , Lactação/genética , Leite/metabolismo , Polimorfismo Genético/genética , Animais , Sequência de Bases , Biomarcadores/metabolismo , Bovinos/metabolismo , China , Feminino , Frequência do Gene , Genótipo , Leucócitos/metabolismo , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita Simples
18.
Ying Yong Sheng Tai Xue Bao ; 31(7): 2227-2235, 2020 Jul.
Artigo em Zh | MEDLINE | ID: mdl-32715685

RESUMO

Methanol, ethyl acetate, and water were used to extract the continuous cropping soils of Panax notoginseng, with the solution/soil ratios of 3:1, 6:1, and 9:1. We investigated the effects of those soil extracts on the growth and population of root-rot pathogens of P. notoginseng. Results showed that the methanol, ethyl acetate and water extracts all promoted mycelial growth of Fusarium oxysporum and Fusarium solani after 72 h of plate culture. The response indices of methanol and ethyl acetate extracts on the growth of F. oxysporum were 14.0%-19.8% and 16.2%-20.2%, being higher than that of water extract (8.9%-14.2%), but without significant difference between diffe-rent extraction ratios. However, methanol extract inhibited the mycelial growth of Alternaria spp. The inhibitory effect was highest at the extraction ratio of 3:1, reaching -33.2% to -38.5%. Ethyl acetate and water extracts did not affect the mycelial growth of Alternaria spp. After four weeks of soil culture, methanol, ethyl acetate and water extracts all increased the F. oxysporum populations. The positive effect of water extract was higher than that of methanol (1.68×104-6.73×104 copies·g-1 dry soil) and ethyl acetate (1.77×104-3.72×104 copies·g-1 dry soil) extracts, being 3.49×106-9.56×106 copies·g-1 dry soil. This increment was weakened along with the increase of extraction ratio. Both water extract and methanol extract with low extraction ratio could increase the F. solani populations, while there were no significant effects of methanol, ethyl acetate and water extracts on the population of Alternaria spp. Therefore, the extracts from continuous P. notoginseng cropping soil showed allopathically promoting effects on the growth and population of root-rot pathogens, F. oxysporum and F. solani, which may be one of the reasons for the occurrence of root rot and other soil-borne diseases in replanted P. notoginseng gardens.


Assuntos
Fusarium , Panax notoginseng , Doenças das Plantas , Raízes de Plantas , Solo
19.
Front Oncol ; 10: 598477, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33425754

RESUMO

TYRO3, AXL, and MERTK constitute the TAM family of receptor tyrosine kinases, which play important roles in tumor growth, survival, cell adhesion, as well as innate immunity, phagocytosis, and immune-suppressive activity. Therefore, targeting both AXL and MERTK kinases may directly impact tumor growth and relieve immunosuppression. We describe here the discovery of INCB081776, a potent and selective dual inhibitor of AXL and MERTK that is currently in phase 1 clinical trials. In cellular assays, INCB081776 effectively blocked autophosphorylation of AXL or MERTK with low nanomolar half maximal inhibitory concentration values in tumor cells and Ba/F3 cells transfected with constitutively active AXL or MERTK. INCB081776 inhibited activation of MERTK in primary human macrophages and partially reversed M2 macrophage-mediated suppression of T-cell proliferation, which was associated with increased interferon-γ production. In vivo, the antitumor activity of INCB081776 was enhanced in combination with checkpoint blockade in syngeneic models, and resulted in increased proliferation of intratumoral CD4+ and CD8+ T cells. Finally, antitumor activity of INCB081776 was observed in a subset of sarcoma patient-derived xenograft models, which was linked with inhibition of phospho-AKT. These data support the potential therapeutic utility of INCB081776 as an immunotherapeutic agent capable of both enhancing tumor immune surveillance and blocking tumor cell survival mechanisms.

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