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Primary effusion lymphoma (PEL) caused by Kaposi sarcoma-associated herpesvirus (KSHV) is an aggressive malignancy with poor prognosis even under chemotherapy. Currently, there is no specific treatment for PEL therefore requiring new therapies. Both histone deacetylases (HDACs) and bromodomain-containing protein 4 (BRD4) have been found as therapeutic targets for PEL through inducing viral lytic reactivation. However, the strategy of dual targeting with one agent and potential synergistic effects have never been explored. In the current study, we first demonstrated the synergistic effect of concurrently targeting HDACs and BRD4 on KSHV reactivation by using SAHA or entinostat (HDACs inhibitors) and (+)-JQ1 (BRD4 inhibitor), which indicated dual blockage of HDACs/BRD4 is a viable therapeutic approach. We were then able to rationally design and synthesize a series of new small-molecule inhibitors targeting HDACs and BRD4 with a balanced activity profile by generating a hybrid of the key binding motifs between (+)-JQ1 and entinostat or SAHA. Upon two iterative screenings of optimized compounds, a pair of epimers, 009P1 and 009P2, were identified to better inhibit the growth of KSHV positive lymphomas compared to (+)-JQ1 or SAHA alone at low nanomolar concentrations, but not KSHV negative control cells or normal cells. Mechanistic studies of 009P1 and 009P2 demonstrated significantly enhanced viral reactivation, cell cycle arrest and apoptosis in KSHV+ lymphomas through dually targeting HDACs and BRD4 signaling activities. Importantly, in vivo preclinical studies showed that 009P1 and 009P2 dramatically suppressed KSHV+ lymphoma progression with oral bioavailability and minimal visible toxicity. These data together provide a novel strategy for the development of agents for inducing lytic activation-based therapies against these viruses-associated malignancies.
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Herpesvirus Humano 8 , Linfoma de Efusión Primaria , Sarcoma de Kaposi , Humanos , Factores de Transcripción/metabolismo , Proteínas Nucleares/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Herpesvirus Humano 8/fisiología , Línea Celular Tumoral , Proteínas de Ciclo Celular/metabolismoRESUMEN
BACKGROUND AND AIM: Baveno VII workshop recommends the use of preemptive TIPS (p-TIPS) in patients with cirrhosis and acute variceal bleeding (AVB) at high- risk of treatment failure. However, the criteria defining "high-risk" have low clinical accessibility or include subjective variables. We aimed to develop and externally validate a model for better identification of p-TIPS candidates. APPROACH AND RESULTS: The derivation cohort included 1554 patients with cirrhosis and AVB who were treated with endoscopy plus drug (n = 1264) or p-TIPS (n = 290) from 12 hospitals in China between 2010 and 2017. We first used competing risk regression to develop a score for predicting 6-week and 1-year mortality in patients treated with endoscopy plus drugs, which included age, albumin, bilirubin, international normalized ratio, white blood cell, creatinine, and sodium. The score was internally validated with the bootstrap method, which showed good discrimination (6 wk/1 y concordance-index: 0.766/0.740) and calibration, and outperformed other currently available models. In the second stage, the developed score was combined with treatment and their interaction term to predicate the treatment effect of p-TIPS (mortality risk difference between treatment groups) in the whole derivation cohort. The estimated treatment effect of p-TIPS varied substantially among patients. The prediction model had good discriminative ability (6 wk/1 y c -for-benefit: 0.696/0.665) and was well calibrated. These results were confirmed in the validation dataset of 445 patients with cirrhosis with AVB from 6 hospitals in China between 2017 and 2019 (6-wk/1-y c-for-benefit: 0.675/0.672). CONCLUSIONS: We developed and validated a clinical prediction model that can help to identify individuals who will benefit from p-TIPS, which may guide clinical decision-making.
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Várices Esofágicas y Gástricas , Derivación Portosistémica Intrahepática Transyugular , Humanos , Várices Esofágicas y Gástricas/etiología , Pronóstico , Modelos Estadísticos , Hemorragia Gastrointestinal/etiología , Hemorragia Gastrointestinal/prevención & control , Cirrosis Hepática/etiología , Derivación Portosistémica Intrahepática Transyugular/efectos adversosRESUMEN
Cancer continues to be a major health concern globally, although the advent of targeted therapy has revolutionized treatment options. Aurora Kinase B is a serine-threonine kinase that has been explored as an oncology therapeutic target for more than two decades. Aurora Kinase B inhibitors show promising biological results in in-vitro and in-vivo experiments. However, there are no inhibitors approved yet for clinical use, primarily because of the side effects associated with Aurora B inhibitors. Several studies demonstrate that Aurora B inhibitors show excellent synergy with various chemotherapeutic agents, radiation therapy, and targeted therapies. This makes it an excellent choice as an adjuvant therapy to first-line therapies, which greatly improves the therapeutic window and side effect profile. Recent studies indicate the role of Aurora B in some deadly cancers with limited therapeutic options, like triple-negative breast cancer and glioblastoma. Herein, we review the latest developments in Aurora Kinase B targeted research, with emphasis on its potential as an adjuvant therapy and its role in some of the most difficult-to-treat cancers.
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Antineoplásicos , Neoplasias , Humanos , Aurora Quinasa B/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Serina-Treonina Quinasas/uso terapéutico , Neoplasias/tratamiento farmacológico , Aurora Quinasa A/uso terapéutico , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/uso terapéuticoRESUMEN
BACKGROUND & AIMS: The optimal timing of measurement and hemodynamic targets of portacaval pressure gradient (PPG) after TIPS remains inconclusive. This study aimed to identify the ideal moment of hemodynamic measurements and the optimal target of PPG in patients undergoing covered TIPS for variceal bleeding. METHODS: Between May 2018 and December 2021, 466 consecutive patients with recurrent variceal bleeding treated with covered TIPS were prospectively included. Post-TIPS PPG were measured immediately (immediate PPG), 24-72 hours (early PPG), and again 1 month (late PPG) after TIPS placement. The agreement among PPGs measured at different time points was assessed by intra-class correlation coefficient (ICC) and Bland-Altman method. The unadjusted and confounder-adjusted effects of PPGs on the clinical outcomes (portal hypertension complications [PHC], overt hepatic encephalopathy [OHE], further decompensation, and death) were assessed using Fine and Gray competing risk regression models. RESULTS: The agreement between early PPG and late PPG (ICC: 0.34) was better than that between immediate PPG and late PPG (ICC: 0.23, p<0.001). Early PPG revealed an excellent predictive value for PHC risk (early PPG ≥ vs <12 mmHg: adjusted HR [95%CI]: 2.17 [1.33-3.55], p=0.002) as well as OHE (0.40 [0.17-0.91], p=0.030) while immediate PPG did not. Late PPG showed a predictive value for PHC risk but not OHE. By targeting the lowest risk of further decompensation, we identified an optimal hemodynamic target with early PPG ranging 11 to 14 mmHg that was associated with a decreased risk of OHE while effectively preventing PHC. CONCLUSIONS: PPG measured 24 to 72 hours after TIPS correlates with long term PPG and clinical outcomes, and hemodynamic target with a PPG 11-14 mmHg reduced encephalopathy but not compromised clinical efficacy. IMPACT AND IMPLICATIONS: The optimal timing of measurement and hemodynamic targets of portacaval pressure gradient (PPG) after transjugular intrahepatic portosystemic shunt (TIPS) remains inconclusive. Here we show that post-TIPS PPG measured at least 24 hours but not immediately after the procedure correlated with long-term PPG and clinical events, therefore should be used for decision making in order to improve clinical outcomes. Targeting post-TIPS PPG at 11-14 mmHg or 20%-50% relative reduction from pre-TIPS baseline that measured 24-72 hours after procedure reduced encephalopathy but not compromised clinical efficacy, therefore could be used to guide TIPS creation and revision in patients with cirrhosis and variceal bleeding undergoing covered TIPS. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, ID: NCT03590288.
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Attack of donor tissues by pre-formed anti-pig antibodies is well known to cause graft failure in xenotransplantation. Genetic engineering of porcine donors to eliminate targets of these pre-formed antibodies coupled with advances in immunosuppressive medicines have now made it possible to achieve extended survival in the pre-clinical pig-to-non-human primate model. Despite these improvements, antibodies remain a risk over the lifetime of the transplant, and many patients continue to have pre-formed donor-specific antibodies even to highly engineered pigs. While therapeutics exist that can help mitigate the detrimental effects of antibodies, they act broadly potentially dampening beneficial immunity. Identifying additional xenoantigens may enable more targeted approaches, such as gene editing, to overcome these challenges by further eliminating antibody targets on donor tissue. Because we have found that classical class I swine leukocyte antigens are targets of human antibodies, we now examine whether related pig proteins may also be targeted by human antibodies. We show here that non-classical class I swine leukocyte proteins (SLA-6, -7, -8) can be expressed at the surface of mammalian cells and act as antibody targets.
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Antígenos Heterófilos , Antígenos de Histocompatibilidad Clase I , Trasplante Heterólogo , Animales , Porcinos , Trasplante Heterólogo/métodos , Antígenos Heterófilos/inmunología , Humanos , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Rechazo de Injerto/inmunología , Animales Modificados GenéticamenteRESUMEN
The role of superficial temporal artery-to-middle cerebral artery (STA-MCA) bypass in acute ischemic stroke (AIS) is contentious, with no evidence in patients with AIS and large vessel occlusion (AIS-LVO). We conducted a cohort study to assess emergency STA-MCA outcomes in AIS-LVO and a meta-analysis to evaluate STA-MCA outcomes in early AIS treatment. From January 2018 to March 2021, we consecutively recruited newly diagnosed AIS-LVO patients, dividing them into STA-MCA and non-STA-MCA groups. To evaluate the neurological status and outcomes, we employed the National Institutes of Health Stroke Scale (NIHSS) during the acute phase and the modified Rankin Scale (mRS) during the follow-up period. Additionally, we conducted a meta-analysis encompassing all available clinical studies to assess the impact of STA-MCA on patients with AIS. In the cohort study (56 patients), we observed more significant neurological improvement in the STA-MCA group at two weeks (p = 0.030). However, there was no difference in the clinical outcomes between the two groups. Multivariable logistic regression identified the NIHSS at two weeks (OR: 0.840; 95% CI: 0.754-0.936, p = 0.002) as the most critical predictor of a good outcome. Our meta-analysis of seven studies indicated a 67% rate for achieving a good outcome (mRS < 3) at follow-up points (95% CI: 57%-77%, I2 = 44.1%). In summary, while the meta-analysis suggested the potential role of STA-MCA bypass in mild to moderate AIS, our single-center cohort study indicated that STA-MCA bypass does not seem to improve the prognosis of patients who suffer from AIS-LVO.
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Revascularización Cerebral , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Enfermedades Vasculares , Humanos , Arteria Cerebral Media/cirugía , Estudios de Cohortes , Arterias Temporales/cirugía , Accidente Cerebrovascular/cirugía , Estudios RetrospectivosRESUMEN
"Zicao" has a long medicinal history and has a variety of pharmacological activities. As the main resource of "zicao" in Tibet, Onosma glomeratum Y. L. Liu (tuan hua dian zi cao), usually used for treating pneumonia in Tibet, has not been reported deeply. In order to determine the main anti-inflammatory active ingredients of Onosma glomeratum Y. L. Liu, in this study, the extracts enriched in naphthoquinones and polysaccharides were optimized prepared form Onosma glomeratum Y. L. Liu by ultrasonic extraction, and reflux extraction, respectively, with Box-Behnken design effect surface method. And their anti-inflammatory abilities were screened on LPS induced A549 cells model, for figuring out the anti-inflammatory active ingredients from Onosma glomeratum Y. L. Liu.The extract enriched naphthoquinone was obtained under following condition: extract with 85% ethanol in a liquid to material ratio of 1:40 g/mL at 30 °C for 30 minutes using ultrasound, leading to the extraction rate of total naphthoquinone as 0.98 ± 0.017%; the extract enriched polysaccharides was prepared as follows: extract 82 minutes at 100 °C with distilled water in a liquid to material ratio of 1:50 g/mL, with extraction rate of polysaccharide as 7.07 ± 0.02%.On the LPS-induced A549 cell model, the polysaccharide extract from Onosma glomeratum Y. L. Liu showed better anti-inflammatory effects than the naphthoquinone extract, indicating the extract enriched in polysaccharides is the anti-inflammatory extract of Onosma glomeratum Y. L. Liu, which could serve as a potential anti-inflammatory extract in medical and food industries in the future.
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Boraginaceae , Naftoquinonas , Lipopolisacáridos , Antiinflamatorios/farmacología , Polisacáridos/farmacologíaRESUMEN
BACKGROUND AND AIMS: Large spontaneous portosystemic shunt (SPSS) is associated with increased risk of HE in patients undergoing transjugular intrahepatic portosystemic shunt (TIPS). This study aimed to evaluate whether prophylactic embolization of large SPSS at the time of TIPS creation could reduce the incidence of post-TIPS HE in patients with cirrhosis and variceal bleeding. APPROACH AND RESULTS: From June 2014 to August 2017, 56 patients with cirrhosis and large SPSS planning to undergo TIPS for the prevention of variceal bleeding were randomly assigned (1:1) to receive TIPS alone (TIPS group, n = 29) or TIPS plus simultaneous SPSS embolization (TIPS+E group, n = 27). The primary endpoint was overt HE. TIPS placement and SPSS embolization was successful in all patients. During a median follow-up of 24 months, the primary endpoint was met in 15 patients (51.7%) in the TIPS group and six patients (22.2%) in the TIPS+E group (p = 0.045). The 2-year cumulative incidence of overt HE was significantly lower in the TIPS+E group compared with the TIPS group (21.2% vs. 48.3%; HR, 0.38; 95% CI, 0.15-0.97; p = 0.043). The 2-year incidence of recurrent bleeding (TIPS+E vs. TIPS, 15.4% vs. 25.1%; p = 0.522), shunt dysfunction (12.3% vs. 18.6%, p = 0.593), death (15.0% vs. 6.9%, p = 0.352), and other adverse events was not significantly different between the two groups. CONCLUSIONS: In patients with cirrhosis treated with TIPS for variceal bleeding, concurrent large SPSS embolization reduced the risk for overt HE without increasing other complications. Concurrent large SPSS embolization should therefore be considered for prophylaxis of post-TIPS HE.
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Várices Esofágicas y Gástricas , Encefalopatía Hepática , Derivación Portosistémica Intrahepática Transyugular , Várices , Várices Esofágicas y Gástricas/complicaciones , Hemorragia Gastrointestinal/etiología , Hemorragia Gastrointestinal/prevención & control , Encefalopatía Hepática/complicaciones , Encefalopatía Hepática/prevención & control , Humanos , Cirrosis Hepática/complicaciones , Derivación Portosistémica Intrahepática Transyugular/efectos adversos , Recurrencia , Resultado del Tratamiento , Várices/complicacionesRESUMEN
The hybrid microcavity composed of different materials shows unique thermal-optical properties such as resonance frequency shift and small thermal noise fluctuations with the temperature variation. Here, we have fabricated the hybrid Si3N4 - TiO2 microring, which decreases the effective thermo-optical coefficients (TOC) from 23.2pm/K to 11.05pm/K due to the opposite TOC of these two materials. In this hybrid microring, we experimentally study the thermal dynamic with different input powers and scanning speeds. The distorted transmission and thermal oscillation are observed, which results from the non-uniform scanning speed and the different thermal relaxation times of the Si3N4 and the TiO2. We calibrate the distorted transmission spectrum for the resonance measurement at the reverse scanning direction and explain the thermal oscillation with a thermal-optical coupled model. Finally, we analyse the thermal oscillation condition and give the diagram about the oscillation region, which has significant guidance for the occurrence and avoidance of the thermal oscillation in practical applications.
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Whispering gallery mode (WGM) resonators provide an important platform for fine measurement thanks to their small size, high sensitivity, and fast response time. Nevertheless, traditional methods focus on tracking single-mode changes for measurement, and a great deal of information from other resonances is ignored and wasted. Here, we demonstrate that the proposed multimode sensing contains more Fisher information than single mode tracking and has great potential to achieve better performance. Based on a microbubble resonator, a temperature detection system has been built to systematically investigate the proposed multimode sensing method. After the multimode spectral signals are collected by the automated experimental setup, a machine learning algorithm is used to predict the unknown temperature by taking full advantage of multiple resonances. The results show the average error of 3.8 × 10-3°C within the range from 25.00°C to 40.00°C by employing a generalized regression neural network (GRNN). In addition, we have also discussed the influence of the consumed data resource on its predicted performance, such as the amount of training data and the case of different temperate ranges between the training and test data. With high accuracy and large dynamic range, this work paves the way for WGM resonator-based intelligent optical sensing.
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Two-dimensional direct numerical simulations of partitioned thermal convection are performed using the thermal lattice Boltzmann method for the Rayleigh number (Ra) of 109 and the Prandtl number (Pr) of 7.02 (water). The influence of the partition walls on the thermal boundary layer is mainly focused on. Moreover, to better describe the spatially nonuniform thermal boundary layer, the definition of the thermal boundary layer is extended. The numerical simulation results show that the gap length significantly affects the thermal boundary layer and Nusselt number (Nu). The gap length and partition wall thickness have a coupled effect on the thermal boundary layer and the heat flux. Based on the shape of the thermal boundary layer distribution, two different heat transfer models are identified at different gap lengths. This study provides a basis for improving the understanding of the effect of partitions on the thermal boundary layer in thermal convection.
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BACKGROUND AND AIMS: Optimal candidates for early transjugular intrahepatic portosystemic shunt (TIPS) in patients with Child-Pugh B cirrhosis and acute variceal bleeding (AVB) remain unclear. This study aimed to test the hypothesis that risk stratification using the Chronic Liver Failure Consortium Acute Decompensation score (CLIF-C ADs) may be useful to identify a subgroup at high risk of mortality or further bleeding that may benefit from early TIPS in patients with Child-Pugh B cirrhosis and AVB. APPROACH AND RESULTS: We analyzed the pooled individual data from two previous studies of 608 patients with Child-Pugh B cirrhosis and AVB who received standard treatment between 2010 and 2017 in China. The concordance index values of CLIF-C ADs for 6-week and 1-year mortality (0.715 and 0.708) were significantly better than those of active bleeding at endoscopy (0.633 [P < 0.001] and 0.556 [P < 0.001]) and other prognostic models. With X-tile software identifying an optimal cutoff value, patients were categorized as low risk (CLIF-C ADs <48), intermediate risk (CLIF-C ADs 48-56), and high risk (CLIF-C ADs >56), with a 5.6%, 16.8%, and 25.4% risk of 6-week death, respectively. Nevertheless, the performance of CLIF-C ADs for predicting a composite endpoint of 6-week death or further bleeding was not satisfactory (area under the receiver operating characteristics curve [AUC], 0.588). A nomogram incorporating components of CLIF-C ADs and albumin, platelet, active bleeding, and ascites significantly improved the prediction accuracy (AUC, 0.725). CONCLUSIONS: In patients with Child-Pugh B cirrhosis and AVB, risk stratification using CLIF-C ADs identifies a subgroup with high risk of death that may derive survival benefit from early TIPS. With improved prediction accuracy for 6-week death or further bleeding, the data-driven nomogram may help to stratify patients in randomized trials. Future external validation of these findings in patients with different etiologies is required.
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Insuficiencia Hepática Crónica Agudizada , Várices Esofágicas y Gástricas/epidemiología , Várices Esofágicas y Gástricas/cirugía , Hemorragia Gastrointestinal/epidemiología , Hemorragia Gastrointestinal/cirugía , Cirrosis Hepática/epidemiología , Derivación Portosistémica Intrahepática Transyugular/métodos , Proyectos de Investigación , Enfermedad Aguda/epidemiología , Adulto , Anciano , China/epidemiología , Comorbilidad , Várices Esofágicas y Gástricas/mortalidad , Femenino , Estudios de Seguimiento , Hemorragia Gastrointestinal/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Nomogramas , Pronóstico , Estudios Prospectivos , Estudios Retrospectivos , Medición de Riesgo , Resultado del TratamientoRESUMEN
Dissipative Kerr solitons in high quality microresonators have attracted much attention in the past few years. They provide ideal platforms for a number of applications. Here, we fabricate the Si3N4 microring resonator with anomalous dispersion for the generation of single soliton and soliton crystal. Based on the strong thermal effect in the high-Q microresonator, the location and strength of the avoided mode crossing in the device can be changed by the intracavity power. Because the existence of the avoided mode crossing can induce the perfect soliton crystal with specific soliton number, we could choose the appropriate pumped resonance mode and appropriate pump power to obtain the perfect soliton crystals on demand.
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OBJECTIVES: Objective response rate (ORR) under mRECIST criteria after transarterial chemoembolization (TACE) is a well-perceived surrogate endpoint of overall survival (OS). However, its optimal time point remains controversial and may be influenced by tumor burden. We aim to investigate the surrogacy of initial/best ORR in relation to tumor burden. METHODS: A total of 1549 eligible treatment-naïve patients with unresectable hepatocellular carcinoma (HCC), Child-Pugh score ≤ 7, and performance status score ≤ 1 undergoing TACE between January 2010 and May 2016 from 17 academic hospitals were retrospectively analyzed. Based on "six-and-twelve" criteria, tumor burden was graded as low, intermediate, and high if the sum of the maximum tumor diameter and tumor number was ≤ 6, > 6 but ≤ 12, and > 12, respectively. RESULTS: Both initial and best ORRs interacted with tumor burden. Initial and best ORRs could equivalently predict and correlate with OS in low (adjusted HR, 2.55 and 2.95, respectively, both p < 0.001; R = 0.84, p = 0.035, and R = 0.97, p = 0.002, respectively) and intermediate strata (adjusted HR, 1.81 and 2.22, respectively, both p < 0.001; R = 0.74, p = 0.023, and R = 0.9, p = 0.002, respectively). For high strata, only best ORR exhibited qualified surrogacy (adjusted HR, 2.61, p < 0.001; R = 0.70, p = 0.035), whereas initial ORR was not significant (adjusted HR, 1.08, p = 0.357; R = 0.22, p = 0.54). CONCLUSIONS: ORR as surrogacy of OS is associated with tumor burden. For patients with low/intermediate tumor burden, initial ORR should be preferred in its early availability upon similar sensitivity, whereas for patients with high tumor burden, best ORR has optimal sensitivity. Timing of OR assessment should be tailored according to tumor burden. KEY POINTS: ⢠This is the first study utilizing individual patient data to comprehensively analyze the surrogacy of ORR with a long follow-up period. ⢠Optimal timing of ORR assessment for predicting survival should be tailored according to tumor burden. ⢠For patients with low and intermediate tumor burden, initial ORR is optimal for its timeliness upon similar sensitivity with best ORR. For patients with high tumor burden, best ORR has optimal sensitivity.
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Carcinoma Hepatocelular , Quimioembolización Terapéutica , Neoplasias Hepáticas , Carcinoma Hepatocelular/patología , Humanos , Neoplasias Hepáticas/patología , Estudios Retrospectivos , Carga TumoralRESUMEN
We theoretically investigate the athermal constructions to cancel the thermorefractive effect of a hybrid Si3N4-TiO2 microring, which merges two materials with opposite thermo-optical coefficients (TOCs). The analytical and numerical results predict that the thermorefractive effect can be reduced under the appropriate parameters. In addition, the soliton state is easily accessed under the athermal condition. The thermorefractive noise due to the fluctuation of the microresonator temperature caused by the heat exchange between the microresonator and the surrounding environment is also suppressed by one order of magnitude, which is critical for the potential applications of soliton microcombs, such as spectroscopy, optical clocks and microwave generation.
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INTRODUCTION: Current guidelines recommend anticoagulation as the mainstay of portal vein thrombosis (PVT) treatment in cirrhosis. However, because of the heterogeneity of PVT, anticoagulation alone does not always achieve satisfactory results. This study aimed to prospectively evaluate an individualized management algorithm using a wait-and-see strategy (i.e., no treatment), anticoagulation, and transjugular intrahepatic portosystemic shunt (TIPS) to treat PVT in cirrhosis. METHODS: Between February 2014 and June 2018, 396 consecutive patients with cirrhosis with nonmalignant PVT were prospectively included in a tertiary care center, of which 48 patients (12.1%) were untreated, 63 patients (15.9%) underwent anticoagulation, 88 patients (22.2%) underwent TIPS, and 197 patients (49.8%) received TIPS plus post-TIPS anticoagulation. The decision of treatment option mainly depends on the stage of liver disease (symptomatic portal hypertension or not) and degree and extension of thrombus. RESULTS: During a median 31.7 months of follow-up period, 312 patients (81.3%) achieved partial (n = 25) or complete (n = 287) recanalization, with 9 (3.1%) having rethrombosis, 64 patients (16.2%) developed major bleeding (anticoagulation-related bleeding in 7 [1.8%]), 88 patients (22.2%) developed overt hepatic encephalopathy, and 100 patients (25.3%) died. In multivariate competing risk regression models, TIPS and anticoagulation were associated with a higher probability of recanalization. Long-term anticoagulation using enoxaparin or rivaroxaban rather than warfarin was associated with a decreased risk of rethrombosis and an improved survival, without increasing the risk of bleeding. However, the presence of complete superior mesenteric vein thrombosis was associated with a lower recanalization rate, increased risk of major bleeding, and poor prognosis. DISCUSSION: In patients with cirrhosis with PVT, the individualized treatment algorithm achieves a high-probability recanalization, with low rates of portal hypertensive complications and adverse events.
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Anticoagulantes/uso terapéutico , Hemorragia/epidemiología , Encefalopatía Hepática/epidemiología , Mortalidad , Vena Porta , Derivación Portosistémica Intrahepática Transyugular/métodos , Trombosis/terapia , Espera Vigilante , Adulto , Anciano , Algoritmos , Terapia Combinada , Enoxaparina/uso terapéutico , Femenino , Hemorragia/inducido químicamente , Humanos , Cirrosis Hepática/complicaciones , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Recurrencia , Rivaroxabán/uso terapéutico , Índice de Severidad de la Enfermedad , Trombosis/etiología , Warfarina/uso terapéuticoRESUMEN
The current evidence is that sensitization to a pig xenograft does not result in the development of antibodies that cross-react with alloantigens, and therefore, sensitization to a pig xenograft would not be detrimental to the outcome of a subsequent allograft. This evidence relates almost entirely to the transplantation of cells or organs from wild-type or α1,3-galactosyltransferase gene-knockout (GTKO) pigs. However, it is not known whether recipients of triple-knockout (TKO) pig grafts who become sensitized to TKO pig antigens develop antibodies that cross-react with alloantigens and thus be detrimental to a subsequent organ allotransplant. We identified a single baboon (B1317) in which no (or minimal) serum anti-TKO pig antibodies could be measured-in our experience unique among baboons. We sensitized it by repeated subcutaneous injections of TKO pig peripheral blood mononuclear cells (PBMCs) in the absence of any immunosuppressive therapy. After TKO pig PBMC injection, there was a transient increase in anti-TKO pig IgM, followed by a sustained increase in IgG binding to TKO cells. In contrast, there was no serum IgM or IgG binding to PBMCs from any of a panel of baboon PBMCs (n = 8). We conclude that sensitization to TKO pig PBMCs in the baboon did not result in the development of antibodies that also bound to baboon cells, suggesting that there would be no detrimental effect of sensitization on a subsequent organ allotransplant.
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Leucocitos Mononucleares , Animales , Animales Modificados Genéticamente , Xenoinjertos , Papio , Porcinos , Trasplante HeterólogoRESUMEN
Pig organ xenotransplantation offers a solution to the shortage of deceased human organs for transplantation. The pathobiological response to a pig xenograft is complex, involving antibody, complement, coagulation, inflammatory, and cellular responses. To overcome these barriers, genetic manipulation of the organ-source pigs has largely been directed to two major aims-(a) deletion of expression of the known carbohydrate xenoantigens against which humans have natural (preformed) antibodies, and (b) transgenic expression of human protective proteins, for example, complement- and coagulation-regulatory proteins. Conventional (FDA-approved) immunosuppressive therapy is unsuccessful in preventing an adaptive immune response to pig cells, but blockade of the CD40:CD154 costimulation pathway is successful. Survival of genetically engineered pig kidneys in immunosuppressed nonhuman primates can now be measured in months. Non-immunological aspects, for example, pig renal function, a hypovolemia syndrome, and rapid growth of the pig kidney after transplantation, are briefly discussed. We suggest that patients on the wait-list for a deceased human kidney graft who are unlikely to receive one due to long waiting times are those for whom kidney xenotransplantation might first be considered. The potential risk of infection, public attitudes to xenotransplantation, and ethical, regulatory, and financial aspects are briefly addressed.
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Trasplante de Riñón , Animales , Animales Modificados Genéticamente , Rechazo de Injerto/prevención & control , Supervivencia de Injerto , Xenoinjertos , Humanos , Riñón , Porcinos , Trasplante HeterólogoRESUMEN
Transition state analogue inhibitor design (TSID) and fragment-based drug design (FBDD) are drug design approaches typically used independently. Methylthio-DADMe-Immucillin-A (MTDIA) is a tight-binding transition state analogue of bacterial 5'-methylthioadenosine nucleosidases (MTANs). Previously, Salmonella enterica MTAN structures were found to bind MTDIA and ethylene glycol fragments, but MTDIA modified to contain similar fragments did not enhance affinity. Seventy-five published MTAN structures were analyzed, and co-crystallization fragments were found that might enhance the binding of MTDIA to other bacterial MTANs through contacts external to MTDIA binding. The fragment-modified MTDIAs were tested with Helicobacter pylori MTAN and Staphylococcus aureus MTANs (HpMTAN and SaMTAN) as test cases to explore inhibitor optimization by potential contacts beyond the transition state contacts. Replacement of a methyl group with a 2'-ethoxyethanol group in MTDIA improved the dissociation constant 14-fold (0.09 nM vs 1.25 nM) for HpMTAN and 81-fold for SaMTAN (0.096 nM vs 7.8 nM). TSID combined with FBDD can be useful in enhancing already powerful inhibitors.
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Adenina/análogos & derivados , Proteínas Bacterianas/metabolismo , Inhibidores Enzimáticos/metabolismo , Purina-Nucleósido Fosforilasa/metabolismo , Pirrolidinas/metabolismo , Adenina/química , Adenina/metabolismo , Bacterias/enzimología , Proteínas Bacterianas/antagonistas & inhibidores , Proteínas Bacterianas/química , Dominio Catalítico , Inhibidores Enzimáticos/química , Polietilenglicoles/química , Polietilenglicoles/metabolismo , Unión Proteica , Purina-Nucleósido Fosforilasa/antagonistas & inhibidores , Purina-Nucleósido Fosforilasa/química , Pirrolidinas/químicaRESUMEN
Diabetic nephropathy (DN) is a severe end-stage kidney disease developed from diabetes mellitus. The involvement of circular RNAs (circRNAs) in modulating DN pathogenesis has been implied, but underlying mechanism is still lacking. In this study, we demonstrated that the expression of circ_0080425 correlated with the DN progression, and exerted positive effect on cell proliferation and fibrosis in mesangial cells. Further assessment suggested that circ_0080425 function as sponge harboring miR-24-3p. Moreover, miR-24-3p negatively correlated with the DN progression, and showed an antagonistic effect to circ_0080425on regulating MCs cell proliferation and fibrosis. Bioinformatics analysis predicted fibroblast growth factor 11 (FGF11) acting as direct downstream target of miR-24-3p. Indeed, the expression of FGF11 was significantly activated by circ_0080425 while suppressed by miR-24-3p. Knockdown of FGF11 resulted in a significant reduced cell proliferation rate and fibrosis. In addition, miR-24-3p inhibitor rescued the suppression of si-circ_0080425 on FGF11, suggesting that circ_0080425 competitive binding to miR-24-3p could release FGF11 from miR-24-3p suppression, which subsequently promoted DN progression.In conclusion, we have reported a novel circ_0080425-miR-24-3p-FGF11 axis, and explored the underlying mechanism in regulating DN pathogenesis.