Interactions of Nanomaterials with Gut Microbiota and Their Applications in Cancer Therapy.

Cancer treatment is a challenge by its incredible complexity. As a key driver and player of cancer, gut microbiota influences the efficacy of cancer treatment. Modalities to manipulate gut microbiota have been reported to enhance antitumor efficacy in some cases. Nanomaterials (NMs) have been comprehensively applied in cancer diagnosis, imaging, and theranostics due to their unique and excellent properties, and their effectiveness is also influenced by gut microbiota. Nanotechnology is capable of targeting and manipulating gut microbiota, which offers massive opportunities to potentiate cancer treatment. Given the complexity of gut microbiota-host interactions, understanding NMs-gut interactions and NMs-gut microbiota interactions are important for applying nanotechnologies towards manipulating gut microbiota in cancer prevention and treatment. In this review, we provide an overview of NMs-gut interactions and NMs-gut microbiota interactions and highlight the influences of gut microbiota on the diagnosis and treatment effects of NMs, further illustrating the potential of nanotechnologies in cancer therapy. Investigation of the influences of NMs on cancer from the perspective of gut microbiota will boost the prospect of nanotechnology intervention of gut microbiota for cancer therapy.

Dose-dependent influence of red blood cell transfusion volume on adverse outcomes in cardiac surgery.

INTRODUCTION: Red blood cell (RBC) transfusion is associated with adverse outcomes, but there are few studies on the RBC volume. This study aimed to evaluate the relationship between intraoperative RBC volume and postoperative adverse outcomes for on-pump cardiac surgery. METHODS: Adult patients undergoing on-pump cardiac surgery from 1 January 2017 to 31 December 2018 were included. Those transfused with more than 6 units of RBC were excluded. The clinical characteristics of four groups with various RBC volume were compared. We analyzed the relationship between RBC volume and adverse outcomes through multivariable logistic regression. RESULTS: 12,143 patients were analyzed, of which 3353 (27.6%) were transfused with 1-6U RBC intraoperatively. The incidence of death, overall morbidity, acute kidney injury and prolonged mechanical ventilation were increased stepwise along with incremental RBC volume. After adjusting for possible confounders, patients transfused with 1-2U were associated with a 1.42-fold risk of death (99% CI, 1.21-2.34, p = 0.01) compared with patients without RBC, patients with 3-4U were associated with a 1.57-fold risk (99% CI, 1.32-2.80, p = 0.005) and patients with 5-6U had a 2.26-fold risk of death (99% CI, 1.65-3.88, p < 0.001). Similarly, the incidence of overall morbidity, acute kidney injury and prolonged mechanical ventilation increased several folds as the RBC numbers increased. CONCLUSIONS: There was a significant dose-dependent influence of incremental intraoperative RBC volume on increased risk of adverse outcomes for on-pump cardiac surgery patients. Patient blood management practice should aim to reduce not only transfusion rate but also the volume of blood use.

Molecular characterization of TRPA1 and its function in temperature preference in Eriocheir sinensis.

Chinese mitten crab (Eriocheir sinensis) is an economically important aquaculture species, and its growth and development are regulated by temperature, but the molecular mechanisms of the responses to temperature remain unclear. Herein, we identified TRPA1 from E. sinensis, a member of the TRP family of heat receptor potential channels, performed RACE cloning and bioinformatics analysis, and investigated the effect of TRPA1 on temperature responses and molting by real-time PCR and RNA interference (RNAi). The open reading frame of Es-TRPA1 is 3660 bp, and the encoded protein has a molecular weight of 136.91 kDa, and is expressed in embryos and juveniles. RNAi-mediated silencing decreased Es-TRPA1 expression in juvenile crabs, molting rate was decreased, mortality was increased, and crabs avoided cold areas (4 °C) much less than control juvenile crabs. The results suggest that Es-TRPA1 is involved in regulating temperature adaptation and molting processes in E. sinensis. The findings lay a foundation for further exploration of temperature regulation mechanisms in E. sinensis and other crustaceans.

Hemostatic alterations during extracorporeal membrane oxygenation in ovine veno-venous and veno-arterial models.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) has salvaged many people's life during global pandemics. However, ECMO is associated with a high incidence of hemostatic complications. This study aims to explore the effects of the ECMO system on the coagulation system in the healthy ovine ECMO model. METHODS: Ten healthy male sheep were included. Five received the veno-arterial ECMO and five received the veno-venous ECMO. Heparin was infused for systemic anticoagulation and was adjusted according to the activated clotting time. Blood routine tests, coagulation factors, anticoagulation proteins, and fibrinolysis markers were tested at the baseline and every 24 h. After weaning, the pump heads were dissected to explore thrombosis. RESULTS: Platelets decreased in the first 72 h and returned to the baseline at the 120th hour. The neutrophils increased in the first 24 h and returned to the baseline at the 48th hour. Factors II, VII, and X decreased in the first 24 h and gradually increased, while factors VIII, IX, XI, and XII decreased in the first 24 h and remained at a low level. The baseline antithrombin was 73.2 ± 14.4% and reduced to 42.6 ± 9.9% at the 168th hour. Pathology showed seven sheep developed thrombus, but no clinically relevant bleeding or thrombosis events occurred. CONCLUSIONS: The study explored hemostatic alterations during ECMO in healthy animal models, which eliminated the confounding under critically ill conditions. The study may provide insights into ECMO hemostatic disorders and aid the design of optimal therapeutic strategies.

AdipoRon Inhibits Neuroinflammation Induced by Deep Hypothermic Circulatory Arrest Involving the AMPK/NF-κB Pathway in Rats.

Deep hypothermic circulatory arrest (DHCA) can induce systemic inflammatory response syndrome, including neuroinflammation. Finding suitable compounds is necessary for attenuating neuroinflammation and avoiding cerebral complications following DHCA. In the present study, we established DHCA rat models and monitored the vital signs during the surgical process. After surgery, we found significantly increased proinflammatory cytokines (IL-6, IL-1ß, and TNF-α) in DHCA rats. Quantitative proteomics analysis was performed for exploring the differentially expressed proteins in hippocampus of DHCA rats and the data showed the adiponectin receptor 1 protein was upregulated. More importantly, administration of AdipoRon, a small-molecule adiponectin receptor agonist, could improve the basic vital signs and attenuate the increased IL-6, IL-1ß, and TNF-α in DHCA rats. Furthermore, AdipoRon inhibits the activation of microglia (M1 state) and promotes their transition to an anti-inflammatory state, via promoting the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK), and downregulating nuclear factor kappa B (NF-κB) in DHCA rats. Consistently, we used LPS-treated BV2 cells to mimic the neuroinflammatory condition and found that AdipoRon dose-dependently decreased cytokines, along with increased phosphorylation of AMPK and downregulated NF-κB. In conclusion, our present data supported that AdipoRon inhibited DHCA-induced neuroinflammation via activating the hippocampal AMPK/NF-κB pathway.

Microinjection-based CRISPR/Cas9 mutagenesis in the decapoda crustaceans Neocaridina heteropoda and Eriocheir sinensis.

CRISPR/Cas9 technology has been applied to many arthropods. However, application of this technology to crustaceans remains limited because of the unique characteristics of embryos. Our group has developed a microinjection system to introduce the CRISPR/Cas9 system into Neocaridina heteropoda embryos (one-cell stage). Using the developed method, we mutated the target gene Nh-scarlet (N. heteropoda scarlet), which functions in eye development and pigmentation. The results showed that both eye color and shape were altered in individuals in which Nh-scarlet was knocked out. Furthermore, this system was also successfully applied to another decapod crustacean, Eriocheir sinensis. DNA sequencing revealed that the zoeae with red eyes had an edited version of Es-scarlet. This study provides a stable microinjection method for freshwater crustaceans, and will contribute to functional genomics studies in various decapods.

Outcomes from adult veno-arterial extracorporeal membrane oxygenation in a cardiovascular disease center from 2009 to 2019.

INTRODUCTION: Extracorporeal membrane oxygenation (ECMO) is an imperative short-term cardiopulmonary support device now. We aimed to provide a single-center experience of veno-arterial (V-A) ECMO management and identify the risk factors of in-hospital mortality. METHODS: We conducted a retrospective review of adult patients who received V-A ECMO between 2009 and 2019 in a cardiovascular disease center. The risk factor analysis of in-hospital mortality was conducted. RESULTS: The study reviewed 236 patients, with an overall survival rate of 68.2%. The survivors' blood lactate concentration is significantly lower than non-survivors [7.4 (7.8) vs 11.1 (9.7), p = 0.002]. Patients who received heart transplantation were with higher in-hospital survival rate. Survivors developed less hepatic dysfunction, acute kidney injury and myocardial damage [23 (14.3%) vs 19 (25.3%), p = 0.039; 81 (50.3%) vs 51 (68%), p = 0.011; 24 (14.9%) vs 22 (29.3%), p = 0.009, respectively], with higher rate of continuous renal replacement therapy (CRRT) [56 (34.8%) vs 53 (70.7%), p < 0.001]. Fewer survivors' 24 hours and total chest drainage was over 1000 mL, and the rate of re-exploration as well as red blood cell and platelet transfusion were lower in survivors. In multivariate analysis, female, pre-ECMO blood lactate concentration, hyperlipidemia, CRRT, and 24 hours chest drainage ⩾ 1000 mL were risk factors of early mortality. CONCLUSIONS: By providing a general description of V-A ECMO practice at a single-center in China. Post-heart transplant graft failure was associated with numerically, the greatest survival in our practice. Furthermore, female sex, pre-ECMO blood lactate concentration, hyperlipidemia, CRRT, and high blood loss in chest drains are predictors of mortality in patients who undergo V-A ECMO.

Safety and Efficacy of a Novel Centrifugal Pump and Driving Devices of the OASSIST ECMO System: A Preclinical Evaluation in the Ovine Model.

Background: Extracorporeal membrane oxygenation (ECMO) provides cardiopulmonary support for critically ill patients. Portable ECMO devices can be applied in both in-hospital and out-of-hospital emergency conditions. We evaluated the safety and biocompatibility of a novel centrifugal pump and ECMO device of the OASSIST ECMO System (Jiangsu STMed Technologies Co., Suzhou, China) in a 168-h ovine ECMO model. Methods: The portable OASSIST ECMO system consists of the control console, the pump drive, and the disposable centrifugal pump. Ten healthy sheep were used to evaluate the OASSIST ECMO system. Five were supported on veno-venous ECMO and five on veno-arterial ECMO, each for 168 h. The systemic anticoagulation was achieved by continuous heparin infusion to maintain the activated clotting time (ACT) between 220 and 250 s. The rotary speed was set at 3,200-3,500 rpm. The ECMO configurations and ACT were recorded every 6 hours (h). The free hemoglobin (fHb), complete blood count, and coagulation action test were monitored, at the 6th h and every 24 h after the initiation of the ECMO. The dissection of the pump head and oxygenator were conducted to explore thrombosis. Results: Ten sheep successfully completed the study duration without device-related accidents. The pumps ran stably, and the ECMO flow ranged from 1.6 ± 0.1 to 2.0 ± 0.11 L/min in the V-V group, and from 1.8 ± 0.1 to 2.4 ± 0.14 L/min in the V-A group. The anticoagulation was well-performed. The ACT was maintained at 239.78 ± 36.31 s, no major bleeding or thrombosis was observed during the ECMO run or in the autopsy. 3/5 in the V-A group and 4/5 in the V-V group developed small thrombus in the bearing pedestal. No obvious thrombus formed in the oxygenator was observed. The hemolytic blood damage was not significant. The average fHb was 0.17 ± 0.12 g/L. Considering hemodilution, the hemoglobin, white blood cell, and platelets didn't reduce during the ECMO runs. Conclusions: The OASSIST ECMO system shows satisfactory safety and biocompatibility for the 168-h preclinical evaluation in the ovine model. The OASSIST ECMO system is promising to be applied in clinical conditions in the future.

An Ovine Model of Awake Veno-Arterial Extracorporeal Membrane Oxygenation.

Background: Large animal models are developed to help understand physiology and explore clinical translational significance in the continuous development of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) technology. The purpose of this study was to investigate the establishment methods and management strategies in an ovine model of VA-ECMO. Methods: Seven sheep underwent VA-ECMO support for 7 days by cannulation via the right jugular vein and artery. The animals were transferred into the monitoring cages after surgery and were kept awake after anesthesia recovery. The hydraulic parameters of ECMO, basic hemodynamics, mental state, and fed state of sheep were observed in real time. Blood gas analysis and activated clotting time (ACT) were tested every 6 h, while the complete blood count, blood chemistry, and coagulation tests were monitored every day. Sheep were euthanized after 7 days. Necropsy was performed and the main organs were removed for histopathological evaluation. Results: Five sheep survived and successfully weaned from ECMO. Two sheep died within 24-48 h of ECMO support. One animal died of fungal pneumonia caused by reflux aspiration, and the other died of hemorrhagic shock caused by bleeding at the left jugular artery cannulation site used for hemodynamic monitoring. During the experiment, the hemodynamics of the five sheep were stable. The animals stayed awake and freely ate hay and feed pellets and drank water. With no need for additional nutrition support or transfusion, the hemoglobin concentration and platelet count were in the normal reference range. The ECMO flow remained stable and the oxygenation performance of the oxygenator was satisfactory. No major adverse pathological injury occurred. Conclusions: The perioperative management strategies and animal care are the key points of the VA-ECMO model in conscious sheep. This model could be a platform for further research of disease animal models, pathophysiology exploration, and new equipment verification.