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1.
Colloids Surf B Biointerfaces ; 192: 111060, 2020 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-32450498

RESUMEN

The blood compatibility of various intravascular (IV) devices (e.g., catheters, sensors, etc.) is compromised by activation of platelets that can cause thrombus formation and device failure. Such devices also carry a high risk of microbial infection. Recently, nitric oxide (NO) releasing polymers/devices have been proposed to reduce these clinical problems. CD47, a ubiquitously expressed transmembrane protein with proven anti-inflammation/anti-platelet properties when immobilized on polymeric surfaces, is a good candidate to complement NO release in both effectiveness and longevity. In this work, we successfully appended CD47 peptides (pepCD47) to the surface of biomedical grade polyurethane (PU) copolymers. SIRPα binding and THP-1 cell attachment experiments strongly suggested that the pepCD47 retains its biological properties when bound to PU films. In spite of the potentially high reactivity of NO toward various amino acid residues in CD47, the efficacy of surface-immobilized pepCD47 to prevent inflammatory cell attachment was not inhibited after being subjected to a high flux of NO for three days, demonstrating excellent compatibility of the two species. We further constructed a CD47 surface immobilized silicone tubing filled with NO releasing S-nitrosoglutathione/ascorbic acid (GSNO/AA) solution for synergistic biocompatibility evaluation. Via an ex vivo Chandler loop model, we demonstrate for the first time that NO release and CD47 modification could function synergistically at the blood/material interface and produce greatly enhanced anti-inflammatory/anti-platelet effects. This concept should be readily implementable to create a new generation of thromboresistant/antimicrobial implantable devices.

2.
Artículo en Inglés | MEDLINE | ID: mdl-32427037

RESUMEN

Purpose: The purpose of this study was to summarize the clinical experience with laparoscopic percutaneous extraperitoneal closure of the internal ring using an epidural needle for inguinal hernias in girls.Material and methods: A total of 462 girls with inguinal hernias participated in this study from January 2013 to June 2019. Laparoscopic percutaneous extraperitoneal closure of the internal ring via an epidural needle was used to treat these patients.Results: All 462 girls with an inguinal hernia successfully underwent laparoscopic surgery. The operative times for unilateral and bilateral inguinal hernias were 15 (11-25) minutes and 23 (18-33) minutes, respectively. All patients were discharged 1-2 days after the operations. During the hospitalization and follow-up periods, none of the following complications were observed: hernia recurrence, umbilical hernia, abdominal wall vascular injury, intestinal injury or bladder injury. However, there were six patients with complications: two cases of poor healing of the umbilical incision, three cases of suture granulomas and one case of groin traction pain and discomfort.Conclusion: Laparoscopic percutaneous extraperitoneal closure of the internal ring using an epidural needle is a safe and feasible method for the treatment of inguinal hernias in girls. This method has the advantages of limited trauma, no scarring and a good cosmetic effect.

3.
J Org Chem ; 2020 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-32401024

RESUMEN

Pd-catalyzed alkoxycarbonylation of alkynes provided a redox-neutral method to selectively access branched/linear α,ß-unsaturated monoesters and 1,4-dicarboxylic acid diesters. Herein, a systematic computational study was performed to elucidate the mechanism and origin of ligand-controlled chemo- and regioselectivities. It is found that the catalytic cycle, including hydrometallation, carbon monoxide insertion, and methanolysis, is more likely than that involving palladium alkoxycarbonyl intermediates. Both hydrometallation and methanolysis stages are important to determine the chemo- and regioselectivities. Hydrometallation proceeds via anti-Markovnikov-selective migratory insertion or Markovnikov-selective ligand-participated electrophilic addition. A flexible bidentate phosphine ligand slows down migratory insertion due to the stronger trans effect of the CO ligand but accelerates the ligand-participated electrophilic addition by adopting better orbital orientations. On the other hand, a ligand-participated mechanism and an unrevealed mechanism involving ketene intermediates can promote methanolysis, whereas ligands with large bite angles or bulky substituents are detrimental to methanolysis. On the basis of these mechanistic foundations, the influence of the flexibility, basicity, bite angle, and steric hindrance of ligands on chemo- and regioselectivities was clarified. The present study provided more universal and deeper mechanistic insights into Pd-catalyzed alkoxycarbonylation reactions and shed light on the superior regulation performance of the bifunctional pyridyl-containing phosphine ligands.

4.
Mol Med ; 26(1): 39, 2020 May 06.
Artículo en Inglés | MEDLINE | ID: mdl-32375633

RESUMEN

BACKGROUND: Ovarian cancer is the most lethal gynecologic cancer. Chemoresistance, especially platinum-resistance, is closely related to metastasis of ovarian cancer, however, the molecular basis by which links chemoresistance and metastasis remains vague. Disordered arachidonic acid (AA) metabolism has been shown to play an important role in the advanced ovarian cancer. This study aimed to explore the underlying mechanism involving eicosanoid metabolism that controlling chemoresistance and metastasis of ovarian cancer. METHODS: Cisplatin (DDP)-resistant SKOV3 (SKOV3-R) cells were constantly induced. Ultra-high-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was performed to determine the AA metabolism in SKOV3 and SKOV3-R cells. Half maximal inhibitory concentration (IC50) and percentage of cell viability were tested using cell counting kit 8 (CCK-8). Realtime quantitative PCR (qPCR) and immunohistochemistry (IHC) were used to evaluate indicated genes and proteins respectively. Bioinformatic analysis and chromatin immunoprecipitation (ChIP) were performed to predict and identify the co-transcription factor of interest genes. Tumor growth and metastasis in the liver were assessed with nude mice by subcutaneously injection of SKOV3-R cells. RESULTS: SKOV3-R cells expressed higher multidrug resistance-associated proteins (MRPs) MRP1 and MRP4. They showed enhanced metastatic ability and produced increased AA-derived eicosanoids. Mechanistically, MRPs, epithelial mesenchymal transition (EMT) markers Snail and Slug, as well as key enzymes involved in AA-metabolism including 12-lipoxygenase (12LOX) were transcribed by the mutual transcription factor SP1 which was consistently upregulated in SKOV3-R cells. Inhibition of SP1 or 12LOX sensitized SKOV3-R cells to DDP and impaired metastasis in vitro and in vivo. CONCLUSION: Our results reveal that SP1-12LOX axis signaling plays a key role in DDP-resistance and metastasis, which provide a new therapeutic target for ovarian cancer.

5.
Nan Fang Yi Ke Da Xue Xue Bao ; 40(1): 131-136, 2020 Jan 30.
Artículo en Chino | MEDLINE | ID: mdl-32376552

RESUMEN

OBJECTIVE: To study sleep quality and cognitive status and their correlation in patients with persistent postural and perceptual dizziness (PPPD). METHODS: We assessed sleep quality and cognitive function among 70 patients with PPPD and 70 age-matched heathy volunteers using Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Pittsburgh Sleep Quality Index and polysomnography (PSG). RESULTS: The patients had a mean MMSE score of 25.10±3.87 and a mean MoCA score of 23.10±6.11, both suggesting mild cognitive impairment of the patients. The mean PSQI score of the patients was 14.60 ± 2.06, suggesting moderate insomnia among the patients. The MMSE scores in 3 dimensions (attention, memory and recall ability) and the dimension scores of MoCA for visual space and executive ability, attention and delayed recall all showed significant positive correlations with PSQI scores for sleep quality, sleep latency, sleep duration, sleep efficiency, sleep disorders and daytime dysfunction. CONCLUSIONS: Moderate sleep disorder and mild cognitive dysfunction are common in PPPD patients. Sleep quality is correlated with cognitive function among these patients, suggesting that improving sleep quality of the patients helps to improve their cognitive function.

6.
Food Chem ; 327: 127058, 2020 May 18.
Artículo en Inglés | MEDLINE | ID: mdl-32464462

RESUMEN

A "turn-on" fluorescence sensor was developed for total detection of fumonisin B1, B2 and B3 (FB1, FB2 and FB3) in maize samples. Rhodamine B isothiocyanate (RBITC) and gold nanoparticles (AuNPs) were employed as the energy donor-acceptor pairs. The intensity of restored fluorescence was inversely proportional to the concentration of the FBs. The limit of detection (LOD) of the sensor for FB1 was 23.80 pg/mL. The coefficient of variation (CV) was both less than 7% for intra- and inter-assay. The linear range was from 51.39 to 2125.92 pg/mL. The average recoveries of FBs from maize samples were ranged from 88.7% to 107.2%. The correlation coefficient of the results between the developed sensor and LC-MS/MS was 0.9970. To fulfill the procedure of the assay, only 46 min was needed. These results suggest that the fluorescence "turn-on" sensor has great potential applications in the analysis of FBs in maize samples.

7.
Med Sci Monit ; 26: e921555, 2020 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-32407297

RESUMEN

BACKGROUND This study aimed to investigate the safety and effectiveness of laparoscopic pyloromyotomy for infants with congenital hypertrophic pyloric stenosis. MATERIAL AND METHODS The clinical data of 233 infants with congenital hypertrophic pyloric stenosis who were treated at our hospital from January 2013 to January 2018 were analyzed retrospectively. The patients were divided into 2 groups: the laparoscopic group (group A, n=126) and the conventional operation group (group B, n=107). RESULTS Laparoscopic surgery was successfully performed in all patients in the laparoscopic group, and none of the surgeries were converted to open surgery. Compared with traditional surgery, laparoscopic surgery has obvious advantages in operation time (29.8±12.9 minutes versus 37.2±17.5 minutes, P=0.012), postoperative feeding time (10.3±2.2 hours versus 15.2±4.1 hours, P=0.035), postoperative hospitalization time (2.8±0.7 days versus 3.5±1.9 days, P=0.013), incision length (0.9±0.2 cm versus 3.3±0.8 cm, P=0.002) and poor wound healing (0 versus 6, P=0.007). No complications, such as bleeding, gastric perforation, duodenal injury, abdominal infection or recurrent vomiting, were observed in the 2 groups. The growth and development (weight and height) of the infants in both groups were normal. CONCLUSIONS Laparoscopic pyloromyotomy has the same safety and effectiveness as the traditional operation and has the advantages of less trauma, faster recovery and cosmetically pleasing incisions.

8.
Artículo en Inglés | MEDLINE | ID: mdl-32426973

RESUMEN

A novel strategy to functionalize transparent flexible plastic films with an optical ion-sensing layer using an inkjet-printing technology is described. The hydrophobic sensing chemicals that include a sodium ionophore, a lipophilic proton chromoionophore, and a lipophilic ion-exchanger are co-deposited onto substrates such as transparent polyester film sheets in the absence of any plasticizer and/or hydrophobic polymer matrix. The inkjet-printing process enables the formation of optode films with nanoscale thickness/roughness that readily facilitate interfacing with aqueous samples. Using a smartphone detector, the colorimetric response of the optodes is shown to reach 95% of equilibrium values within 100 s in response to different concentrations of sodium ions, which is more rapid than traditional ion-selective optodes based on plasticized PVC films as the sensing layer. The new optodes also exhibit high selectivity to Na+ over interfering ions including K+, Ca2+, and Mg2+. Chemical leaching experiments show that the highly hydrophobic optode components remain in place on the plastic substrate surface. Hence, excellent sensor stability and fully reversible optical responses are obtained, which is essential for potential continuous monitoring applications. Further testing of the sensors with undiluted human sweat samples is shown to yield accurate values for sodium concentrations. Therefore, the use of plasticizer-free ion-selective optode nanolayers that enable highly selective ion sensing on a clear plastic support is likely to expand the range of available chemical sensors suited for preparing wearable real-time sweat analysis devices.

9.
Artículo en Inglés | MEDLINE | ID: mdl-32469505

RESUMEN

Carbon-supported Pt-Co (Pt-Co/C) nanoparticles with a high Pt loading are regarded as promising cathode catalysts for practical applications of proton exchange membrane fuel cells (PEMFCs). Unfortunately, with high loading, it is difficult to improve the catalytic durability while maintaining the particle size between 2-5 nm to ensure the initial catalytic activity. Thus, it is of great significance to prepare high-loading Pt-Co/C catalysts with enhanced activity and durability. Herein, we proposed an efficient way to prepare high-Pt-loading (>50 wt.%) Pt-Co/C catalysts without using any further surfactants. Furthermore, due to the one-step selective acid etching and surface Au modification, the as-prepared catalysts only need to undergo thermal treatment at as low as 150℃ to achieve a surface structure rich of Pt and Au. The average particle size of the as-prepared Au-Pt-Co/C-0.015 is 3.42 nm and the Pt loading of it is up to 50.2 wt.%. The atomic ratio of Pt, Co and Au is 94:5:1. The mass activity (MA) is nearly 1.9 times that of Pt/C (60 wt.%, JM) and the specific activity (SA) is also improved. The MA loss after the 30,000-cycle accelerated degradation test (ADT) is only 9.4%. The remarkable durability is mainly due to the surface Au modification, which can restrict the dissolution of Pt and Co. This research provides an effective synthesis strategy to prepare high-loading carbon-supported Pt-based catalysts beneficial to practical PEMFC applications.

10.
BMC Psychiatry ; 20(1): 266, 2020 May 29.
Artículo en Inglés | MEDLINE | ID: mdl-32471440

RESUMEN

BACKGROUND: Limited work has been done to explain how work-family conflict is related to anxiety symptoms and the roles of emotional exhaustion and social support may play. METHODS: Based on a sample of 764 female nurses and physicians, a model was tested in which emotional exhaustion served as a mediator and social support was regarded as a moderator between work-family conflict and anxiety symptoms. RESULTS: This current study supported a moderated mediation model where the relationship between work-family conflict and anxiety symptoms via emotional exhaustion was weakest for female medical staff who reported high levels of social support. CONCLUSIONS: This study contribute to providing an understanding of how and when work-family conflict affects anxiety symptoms. The results implicate a wide range of interventions aimed at promoting mental wellbeing among female medical staff for policymakers and individuals.

11.
Medicine (Baltimore) ; 99(20): e20212, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32443347

RESUMEN

BACKGROUND: Although several previous studies have reported the efficacy of remifentanil in cesarean section (CS) under general anesthesia, no study has specifically addressed its neonatal effect (NE) in CS under general anesthesia systematically. Thus, this study will systematically investigate the NE of remifentanil in CS under general anesthesia. METHODS: Electronic databases including MEDLINE, EMBASE, Cochrane Library, Web of Science, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure will be systematically retrieved with the assistance of a specialist librarian to check randomized controlled trials reporting NE in CS under general anesthesia. We will retrieve all electronic databases from their initial time to March 20, 2020 without restrictions of language. All process of study selection, data extraction, and risk of bias evaluation will be carried out by 2 independent authors. We will invite another senior expert to solve the problems that arise between 2 authors. Data will be pooled and analyzed using RevMan V.5.3 software. RESULTS: Outcomes consist of assessment of neonatal adaptation, requirements for postoperative respiratory support of neonates, systolic and diastolic noninvasive blood pressure, mean blood pressure, heart rate, electrocardiography, umbilical cord blood gas analysis, and adverse events. CONCLUSION: This study will present evidence of the NE of remifentanil in CS under general anesthesia. This information may inform benefits of intervention to guide the usage of remifentanil in CS under general anesthesia. STUDY REGISTRATION: INPLASY202040028.

12.
Medicine (Baltimore) ; 99(20): e20242, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32443360

RESUMEN

BACKGROUND: Knee osteoarthritis (KOA) is a disabling joint disease with an increasingly prevalence among the older individuals. Tai Chi, one of the ancient meditative movements, has been recognized to have clinical benefits for KOA. We aim to evaluate the efficacy and safety of Tai Chi for patients with KOA through this systematic review. METHODS: Five English databases (Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, AMED, and CINAHL), 4 Chinese databases (CBM, CNKI, CQVIP, and Wanfang), and 5 clinical trial registration databases (ClinicalTrials.gov, ANZCTR, EU-CTR, ChiCTR, and ICTRP) will be searched from establishment of the database until November 31, 2019. Grey literature will be searched in SIGLE, Grey Net, Microsoft Academic, Google Scholar, Open Aire, World Wide Science.org, and WorldCat. There will be no restrictions on language. The randomized controlled trials of Tai Chi training for patients with KOA will be included. The primary outcome will be assessed according to the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Meta-analysis will be conducted with the use of RevMan 5.3. The specific process will refer to the Cochrane Handbook 5.1 for Systematic Review. RESULTS: High-quality synthesis of current evidence on the efficacy and safety of Tai Chi training for KOA will be provided in this study. CONCLUSION: This systematic review aims to present evidence for whether Tai Chi training is an effective intervention which can improve both physical condition and life quality in patients suffering KOA.

13.
Int J Mol Sci ; 21(10)2020 May 20.
Artículo en Inglés | MEDLINE | ID: mdl-32443726

RESUMEN

In the spinal cord, excitatory V2a and inhibitory V2b interneurons are produced together by the final division of common P2 progenitors. During V2a and V2b diversification, Tal1 is necessary and sufficient to promote V2b differentiation and Vsx2 suppresses the expression of motor neuron genes to consolidate V2a interneuron identity. The expression program of Tal1 is triggered by a Foxn4-driven regulatory network in the common P2 progenitors. Why the expression of Tal1 is inhibited in V2a interneurons at the onset of V2a and V2b sub-lineage diversification remains unclear. Since transcription repressor Vsx1 is expressed in the P2 progenitors and newborn V2a cells in zebrafish, we investigated the role of Vsx1 in V2a fate specification during V2a and V2b interneuron diversification in this species by loss and gain-of-function experiments. In vsx1 knockdown embryos or knockout Go chimeric embryos, tal1 was ectopically expressed in the presumptive V2a cells, while the generation of V2a interneurons was significantly suppressed. By contrast, in vsx1 overexpression embryos, normal expression of tal1 in the presumptive V2b cells was suppressed, while the generation of V2a interneuron was expanded. Chromatin immunoprecipitation and electrophoretic mobility shift assays in combination with core consensus sequence mutation analysis further revealed that Vsx1 can directly bind to tal1 promoter and repress tal1 transcription. These results indicate that Vsx1 can directly repress tal1 transcription and plays an essential role in defining V2a interneuron sub-lineage during V2a and V2b sub-lineage diversification in zebrafish.

14.
Artículo en Inglés | MEDLINE | ID: mdl-32447486

RESUMEN

PURPOSE: Currently, the routine screening program has insufficient capacity for the early diagnosis of lung cancer. Therefore, a type of chitosan-molecular beacon (CS-MB) probe was developed to recognize the miR-155-5p and image the lung cancer cells for the early diagnosis. METHODS: Based on the molecular beacon (MB) technology and nanotechnology, the CS-MB probe was synthesized self-assembly. There are four types of cells-three kinds of animal models and one type of histopathological sections of human lung cancer were utilized as models, including A549, SPC-A1, H446 lung cancer cells, tumor-initiating cells (TICs), subcutaneous and lung xenografts mice, and lox-stop-lox(LSL) K-ras G12D transgenic mice. The transgenic mice dynamically displayed the process from normal lung tissues to atypical hyperplasia, adenoma, carcinoma in situ, and adenocarcinoma. The different miR-155-5p expression levels in these cells and models were measured by quantitative real-time polymerase chain reaction (qRT-PCR). The CS-MB probe was used to recognize the miR-155-5p and image the lung cancer cells by confocal microscopy in vitro and by living imaging system in vivo. RESULTS: The CS-MB probe could be used to recognize the miR-155-5p and image the lung cancer cells significantly in these cells and models. The fluorescence intensity trends detected by the CS-MB probe were similar to the expression levels trends of miR-155 tested by qRT-PCR. Moreover, the fluorescence intensity showed an increasing trend with the tumor progression in the transgenic mice model, and the occurrence and development of lung cancer were dynamically monitored by the differen fluorescence intensity. In addition, the miR-155-5p in human lung cancer tissues could be detected by the miR-155-5p MB. CONCLUSION: Both in vivo and in vitro experiments demonstrated that the CS-MB probe could be utilized to recognize the miR-155-5p and image the lung cancer cells. It provided a novel experimental and theoretical basis for the early diagnosis of the disease. Also, the histopathological sections of human lung cancer research laid the foundation for subsequent preclinical studies. In addition, different MBs could be designed to detect other miRNAs for the early diagnosis of other tumors.

15.
Mol Med Rep ; 22(1): 317-327, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-32377749

RESUMEN

Facial jaw muscle is involved in the occurrence, development, treatment and maintenance of maxillofacial deformities. The structure and function of this tissue can be altered by changes in external stimuli, and orthodontists can regulate its reconstruction using orthopedic forces. The PI3K/Akt signaling pathway is most well­known for its biological functions in cell proliferation, survival and apoptosis. In the present study, the effects of the PI3K/Akt signaling pathway in cyclic stretch­induced myoblast apoptosis were investigated. For this purpose, L6 rat myoblasts were cultured under mechanical stimulation and treated with the PI3K kinase inhibitor, LY294002, to elucidate the role of the PI3K/Akt signaling pathway. Cells were stained with Hoechst 33258 to visualize morphological changes and apoptosis of myoblasts, and western blotting was performed to detect expression of Akt, phosphorylated (p)­Akt (Ser473), glycogen synthase kinase 3ß (GSK­3ß) and p­GSK­3ß (Ser9). After addition of PI3K inhibitor, the expression of total Akt and GSK­3ß did not significantly differ among groups; however, the levels of p­Akt and p­GSK­3ß were lower in inhibitor­treated groups than in those treated with loading stress alone. In addition, the rate of apoptosis in myoblasts subjected to cyclic stretch increased in a time­dependent manner, peaking at 24 h. Collectively, it was also demonstrated that the PI3K/Akt/GSK­3ß pathway plays an important role in stretch­induced myoblast apoptosis.

16.
Am Surg ; 86(4): 334-340, 2020 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-32391757

RESUMEN

Different kinds of complications after splenectomy in hepatolenticular degeneration patients with hypersplenism have been reported in the past decades, but studies on pancreatic fistula and the corresponding targeted prevention and treatment after splenectomy still remain much unexplored. The present work investigated the pathogenic factors of pancreatic fistula after splenectomy and the variation tendency of amylase in drainage fluid, aiming to verify the significance of monitoring amylase in the abdominal drainage fluid in the early diagnosis of pancreatic fistula after splenectomy. One hundred sixty-seven patients with hepatolenticular degeneration and hypersplenism who underwent splenectomy in the First Affiliated Hospital of Anhui University of Traditional Chinese Medicine from January 2016 to August 2018 were selected and analyzed. The amylase in the abdominal drainage fluid was monitored routinely after splenectomy. We also conducted the statistics on the incidence of different types of pancreatic fistula and analyzed the influence factors of pancreatic fistula formation. After splenectomy, biochemical fistula occurred in 11 patients (6.6%), grade B fistula in six patients (3.6%), grade C fistula in one patient (0.6%), and the incidence of pancreatic fistula was 4.2 per cent (biochemical fistula excluded). The amylase in the peritoneal drainage fluid was closely concerned with the incidence of pancreatic fistula according to our statistics. Furthermore, by analyzing the different influence factors of pancreatic fistula, Child-Pugh grading of liver function (P = 0.041), pancreatic texture (P = 0.029), degree of splenomegaly (P = 0.003), and operative method (P = 0.001) were supposed to be closely related to the formation of pancreatic fistula. Monitoring of amylase in peritoneal drainage fluid is regarded as an important physiological parameter in the early diagnosis of pancreatic fistula after splenectomy, which provides effective clinical reference and plays a significant role in preventing the occurrence and development of pancreatic fistula.


Asunto(s)
Amilasas/análisis , Líquido Ascítico/química , Degeneración Hepatolenticular/cirugía , Fístula Pancreática/etiología , Complicaciones Posoperatorias/epidemiología , Esplenectomía/efectos adversos , Esplenomegalia/cirugía , Adolescente , Adulto , Anciano , Biomarcadores/análisis , Niño , Drenaje , Femenino , Degeneración Hepatolenticular/complicaciones , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Monitoreo Fisiológico , Fístula Pancreática/epidemiología , Fístula Pancreática/prevención & control , Esplenomegalia/etiología , Adulto Joven
17.
Nat Commun ; 11(1): 2506, 2020 May 19.
Artículo en Inglés | MEDLINE | ID: mdl-32427851

RESUMEN

The genetic basis and corresponding clinical relevance of prolactinomas remain poorly understood. Here, we perform whole genome sequencing (WGS) on 21 patients with prolactinomas to detect somatic mutations and then validate the mutations with digital polymerase chain reaction (PCR) analysis of tissue samples from 227 prolactinomas. We identify the same hotspot somatic mutation in splicing factor 3 subunit B1 (SF3B1R625H) in 19.8% of prolactinomas. These patients with mutant prolactinomas display higher prolactin (PRL) levels (p = 0.02) and shorter progression-free survival (PFS) (p = 0.02) compared to patients without the mutation. Moreover, we identify that the SF3B1R625H mutation causes aberrant splicing of estrogen related receptor gamma (ESRRG), which results in stronger binding of pituitary-specific positive transcription factor 1 (Pit-1), leading to excessive PRL secretion. Thus our study validates an important mutation and elucidates a potential mechanism underlying the pathogenesis of prolactinomas that may lead to the development of targeted therapeutics.

18.
Nature ; 2020 May 26.
Artículo en Inglés | MEDLINE | ID: mdl-32454513

RESUMEN

The emerging coronavirus SARS-CoV-2 pandemic presents a global health emergency in urgent need of interventions1-3. SARS-CoV-2 entry into the target cells depends on binding between the receptor-binding domain (RBD) of the viral Spike protein and the ACE2 cell receptor2,4-6. Here, we report the isolation and characterization of 206 RBD-specific monoclonal antibodies derived from single B cells of eight SARS-CoV-2 infected individuals. We identified antibodies with potent anti-SARS-CoV-2 neutralization activity that correlates with their competitive capacity with ACE2 for RBD binding. Surprisingly, neither the anti-SARS-CoV-2 antibodies nor the infected plasma cross-reacted with SARS-CoV or MERS-CoV RBDs, although substantial plasma cross-reactivity to their trimeric Spike proteins was found. Crystal structure analysis of RBD-bound antibody revealed steric hindrance that inhibits viral engagement with ACE2 and thereby blocks viral entry. These findings suggest that anti-RBD antibodies are viral species-specific inhibitors. The antibodies identified here may be candidates for the development of SARS-CoV-2 clinical interventions.

19.
Haematologica ; 2020 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-32414851

RESUMEN

FLT3 internal tandem duplication (FLT3-ITD) mutations account for ~25% of adult acute myeloid leukemia cases and are associated with poor prognosis. Venetoclax, a selective BCL-2 inhibitor, has limited monotherapy activity in relapsed/refractory acute myeloid leukemia with no responses observed in a small subset of FLT3-ITD+ patients. Further, FLT3-ITD mutations emerged at relapse following venetoclax monotherapy and combination therapy suggesting a potential mechanism of resistance. Therefore, we investigated the convergence of FLT3-ITD signaling on the BCL-2 family proteins and determined combination activity of venetoclax and FLT3-ITD inhibition in preclinical models. In vivo, venetoclax combined with quizartinib, a potent FLT3 inhibitor, showed greater anti-tumor efficacy and prolonged survival compared to monotherapies. In a patient-derived FLT3-ITD+ xenograft model, cotreatment with venetoclax and quizartinib at clinically relevant doses had greater anti-tumor activity in the tumor microenvironment compared to quizartinib or venetoclax alone. Use of selective BCL-2 family inhibitors further identified a role for BCL-2, BCL-XL and MCL-1 in mediating survival in FLT3-ITD+ cells in vivo and highlighted the need to target all three proteins for greatest anti-tumor activity. Assessment of these combinations in vitro revealed synergistic combination activity for quizartinib and venetoclax but not for quizartinib combined with BCL-XL or MCL-1 inhibition. FLT3-ITD inhibition was shown to indirectly target both BCL-XL and MCL-1 through modulation of protein expression, thereby priming cells toward BCL-2 dependence for survival. These data demonstrate that FLT3-ITD inhibition combined with venetoclax has impressive anti-tumor activity in FLT3-ITD+ acute myeloid leukemia preclinical models and provides strong mechanistic rational for clinical studies.

20.
Environ Pollut ; 260: 113873, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32369892

RESUMEN

Cadmium (Cd), a heavy metal contaminant, exists in humans and animals throughout life and closely associate with severe hepatotoxicity. Selenium (Se) has been recognized as an effective chemo-protectant of Cd, but the underlying mechanisms remain unclear. The objective of the present study is to illustrate the antagonistic effect of Se against Cd-induced hepatotoxicity. Primary hepatocytes were cultured in the presence of 5 µM Cd, 1 µM Se and the mixture of 1 µM Se and 5 µM Cd for 24 h. Cell viability and morphology, antioxidant status, endoplasmic reticulum (ER) stress response and selenotranscriptome were assessed. It was observed that Se treatment dramatically alleviated Cd-induced hepatocytes death and morphological change. Simultaneously, Se mitigated Cd-induced oxidative stress by reducing ROS production, increasing reduced glutathione (GSH) level and increasing selenoenzyme (glutathione peroxidase, GPX) activity. Cd induced hepatotoxicity via disordering ER-resident selenoproteins transcription and triggering ER stress and unfolded protein response. Supplementary Se evidently relieved hepatocytes injury via modulating ER-resident selenoproteins transcription to inhibit ER stress. Collectively, our findings showed a potential protection of Se against Cd-induced hepatotoxicity via suppressing ER stress response.


Asunto(s)
Cadmio/toxicidad , Retículo Endoplásmico/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Selenio/farmacología , Selenoproteínas/biosíntesis , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas , Retículo Endoplásmico/metabolismo , Estrés del Retículo Endoplásmico
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