Threshold effect of physical exercise on its association to diabetes mellitus in short sleep population: evidence from a nationwide study.

Background: The prevalence of diabetes mellitus (DM) is a significant public health concern, especially among individuals with short sleep duration. Understanding the relationship between physical exercise and DM in this population is crucial for developing effective prevention strategies. However, the presence of a potential threshold effect of exercise on DM risk remains unclear. Methods: Using data from the National Health and Nutrition Examination Survey (NHANES) spanning from 2007 to 2018, this population-based study investigated the association between physical exercise and DM in individuals with short sleep duration (no more than 7 hours per night). Weighted logistic regression analyses were conducted, adjusting for demographic and lifestyle factors. Additionally, a two-piecewise linear regression model was employed to identify any threshold effect of exercise on DM risk. Results: This study included 15,092 participants identified with short sleep duration. Demographic characteristics stratified by DM status indicate higher prevalence among certain groups, such as middle-aged and older adults, males, and non-Hispanic Whites. The analysis revealed an inverse association between exercise levels and DM prevalence among the short sleep population. In the fully adjusted model, individuals engaging in sufficient exercise (> 600 MET-minutes/week) exhibited significantly reduced odds of developing DM [OR (95% CI): 0.624(0.527,0.738), p < 0.001]. Furthermore, the segmented regression model identified an inflection point at 2000 MET-minutes/week, below which a significant correlation between exercise and DM was observed. Conclusions: This study provides evidence of a threshold effect of physical exercise on its association with DM in individuals with short sleep duration. Tailored exercise interventions targeting this population may help mitigate DM risk and improve overall health outcomes. Further research is warranted to validate these findings and explore optimal exercise thresholds for DM prevention strategies.

Effect of acupuncture combined with rehabilitation training on sensory impairment of patients with stroke: a network meta-analysis.

BACKGROUND: The refractory and disabling nature of sensory disorders after stroke seriously affects patients' daily lives and reduces hospital turnover. Acupuncture, as an alternative therapy, is commonly used in combination with rehabilitation training to improve sensory disorders. To compare the effects of different acupuncture-related treatments combined with rehabilitation training on sensory impairment and the daily living ability of patients with stroke, we conducted a network meta-analysis to provide evidence-based findings for clinical practice. METHODS: Randomized controlled trials on the treatment of sensory disorders in patients with stroke were systematically retrieved from several databases, including China National Knowledge Infrastructure (CNKI), China Science and Technology Journal(VIP), Wanfang Database, Chinese Biological Medical (CBM), PubMed, Embase, Web of Science, Cochrane Library, and Clinical trials. The retrieval period ranged from January 2012 to December 2023. Two independent reviewers screened the included literature, extracted the data, and assessed the risk quality using Cochrane Handbook 5.1.0 and ReviewManager 5.4.1. Stata16.0 software was employed for data analysis. The study protocol was registered in PROSPERO: CRD42023389180. RESULTS: After screening, 20 studies were included, involving a total of 1999 subjects. The network meta-analysis results indicate that, compared to standard rehabilitation, acupuncture plus massage plus rehabilitation showed the most significant reduction in Numbness Syndrome Scores (MD = -0.71(-1.11,-0.31)). Acupuncture combined with rehabilitation demonstrated the most substantial improvement in Sensory Impairment Scores (MD = -0.59,(-0.68,-0.51)) and daily living ability of patients (MD = 17.16,(12.20,22.12)). CONCLUSIONS: In comparison to standard rehabilitation, the combination of acupuncture-related treatments and modern rehabilitation training not only improves the symptoms of sensory impairment and numbness after stroke but also enhances the daily living ability of patients, especially when acupuncture is combined with rehabilitation. However, further demonstration is required to strengthen these conclusions.

Distribution of bacteria and risk factors in patients with multidrug-resistant pneumonia in a single center rehabilitation ward.

Stroke patients may have dysphagia and frequent aspiration increasing exposure to antibiotics and the chance of multidrug-resistant (MDR) bacteria infection. This study investigated clinical risk factors and related antibiotic use of MDR bacteria infection in stroke patients in the rehabilitation ward, hoping that it can help prevent and reduce the condition of MDR bacteria. A retrospective cohort study was conducted using the database of stroke patients with pneumonia admitted to the rehabilitation ward from January 1, 2020, to June 30, 2022. The selected stroke patients were divided into the MDR and non-MDR groups. Analyze the infection bacteria of the 2 groups. Forward logistic regression was applied to identify possible independent MDR bacteria infection risk factors. A total of 323 patients were included. The top 3 common MDR pathogens were Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii. Almost all Pseudomonas aeruginosa and Acinetobacter baumannii are resistant to ertapenem. National Institute of Health stroke scale at admission was associated with MDR bacteria infection pneumonia (OR [odds ratio] = 1.078, 95%CI [1.017, 1.142]). Long-term tracheotomy (OR = 2.695, 95%CI [1.232, 5.897]), hypoalbuminemia (OR = 473, 95%CI [1.318, 4.642]), and bilateral cerebral hemisphere stroke (OR = 4.021, 95%CI [2.009, 8.048]) were significant clinical risk factors of MDR pneumonia after stroke. The detection rate of MDR bacteria has increased. Understanding the distribution and drug resistance of MDR bacteria in stroke patients with pneumonia in the neurological rehabilitation ward and the related susceptibility of MDR bacteria infection is necessary. This way, the treatment plan can be adjusted more timely, avoiding the abuse of antibiotics.

Discovery of 1H-Imidazo[4,5-b]pyridine Derivatives as Potent and Selective BET Inhibitors for the Management of Neuropathic Pain.

Neuropathic pain (NP) is an intolerable pain syndrome that arises from continuous inflammation and excitability after nerve injury. Only a few NP therapeutics are currently available, and all of them do not provide adequate pain relief. Herein, we report the discovery of a selective and potent inhibitor of the bromodomain and extra-terminal (BET) proteins for reducing neuroinflammation and excitability to treat NP. Starting with the screening hit 1 from an in-house compound library, iterative optimization resulted in the potent BET inhibitor DDO-8926 with a unique binding mode and a novel chemical structure. DDO-8926 exhibits excellent BET selectivity and favorable drug-like properties. In mice with spared nerve injury, DDO-8926 significantly alleviated mechanical hypersensitivity by inhibiting pro-inflammatory cytokine expression and reducing excitability. Collectively, these results implicate that DDO-8926 is a promising agent for the treatment of NP.

Choice of anaesthesia in microelectrode recording-guided deep-brain stimulation for Parkinson's disease (CHAMPION): study protocol for a single-centre, open-label, non-inferiority randomised controlled trial.

INTRODUCTION: Deep brain stimulation (DBS) implantation under general anaesthesia (GA) has been applied to patients with Parkinson's disease (PD) with severe comorbidities or disabling off-medication symptoms. However, general anaesthetics may affect intraoperative microelectrode recording (MER) to varying degrees. At present, there are few studies on the effects of sedatives or general anaesthetics on multiunit activity characteristics performed by MER in patients with PD during DBS. Therefore, the effect of the choice of anaesthesia on MER remains unclear. METHODS/DESIGN: This is a prospective randomised controlled, non-inferiority study that will be carried out at Beijing Tiantan Hospital, Capital Medical University. Patients undergoing elective bilateral subthalamic nucleus (STN)-DBS will be enrolled after careful screening for eligibility. One hundred and eighty-eight patients will be randomised to receive either conscious sedation (CS) or GA at a 1:1 ratio. The primary outcome is the proportion of high normalised root mean square (NRMS) recorded by the MER signal. ETHICS AND DISSEMINATION: The study was approved by the Ethics Committee of Beijing Tiantan Hospital of Capital Medical University (KY2022-147-02). Negative study results will indicate that GA using desflurane has a non-inferior effect on MER during STN-DBS compared with CS. The results of this clinical trial will be presented at national or international conferences and submitted to a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT05550714.

CIRP attenuates acute kidney injury after hypothermic cardiovascular surgery by inhibiting PHD3/HIF-1α-mediated ROS-TGF-ß1/p38 MAPK activation and mitochondrial apoptotic pathways.

BACKGROUND: The ischemia-reperfusion (IR) environment during deep hypothermic circulatory arrest (DHCA) cardiovascular surgery is a major cause of acute kidney injury (AKI), which lacks preventive measure and treatment. It was reported that cold inducible RNA-binding protein (CIRP) can be induced under hypoxic and hypothermic stress and may have a protective effect on multiple organs. The purpose of this study was to investigate whether CIRP could exert renoprotective effect during hypothermic IR and the potential mechanisms. METHODS: Utilizing RNA-sequencing, we compared the differences in gene expression between Cirp knockout rats and wild-type rats after DHCA and screened the possible mechanisms. Then, we established the hypothermic oxygen-glucose deprivation (OGD) model using HK-2 cells transfected with siRNA to verify the downstream pathways and explore potential pharmacological approach. The effects of CIRP and enarodustat (JTZ-951) on renal IR injury (IRI) were investigated in vivo and in vitro using multiple levels of pathological and molecular biological experiments. RESULTS: We discovered that Cirp knockout significantly upregulated rat Phd3 expression, which is the key regulator of HIF-1α, thereby inhibiting HIF-1α after DHCA. In addition, deletion of Cirp in rat model promoted apoptosis and aggravated renal injury by reactive oxygen species (ROS) accumulation and significant activation of the TGF-ß1/p38 MAPK inflammatory pathway. Then, based on the HK-2 cell model of hypothermic OGD, we found that CIRP silencing significantly stimulated the expression of the TGF-ß1/p38 MAPK inflammatory pathway by activating the PHD3/HIF-1α axis, and induced more severe apoptosis through the mitochondrial cytochrome c-Apaf-1-caspase 9 and FADD-caspase 8 death receptor pathways compared with untransfected cells. However, silencing PHD3 remarkably activated the expression of HIF-1α and alleviated the apoptosis of HK-2 cells in hypothermic OGD. On this basis, by pretreating HK-2 and rats with enarodustat, a novel HIF-1α stabilizer, we found that enarodustat significantly mitigated renal cellular apoptosis under hypothermic IR and reversed the aggravated IRI induced by CIRP defect, both in vitro and in vivo. CONCLUSION: Our findings indicated that CIRP may confer renoprotection against hypothermic IRI by suppressing PHD3/HIF-1α-mediated apoptosis. PHD3 inhibitors and HIF-1α stabilizers may have clinical value in renal IRI.

Novel Hydrogen Sulfide Hybrid Derivatives of Keap1-Nrf2 Protein-Protein Interaction Inhibitor Alleviate Inflammation and Oxidative Stress in Acute Experimental Colitis.

Ulcerative colitis (UC) is an idiopathic inflammatory disease of unknown etiology possibly associated with intestinal inflammation and oxidative stress. Molecular hybridization by combining two drug fragments to achieve a common pharmacological goal represents a novel strategy. The Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway provides an effective defense mechanism for UC therapy, and hydrogen sulfide (H2S) shows similar and relevant biological functions as well. In this work, a series of hybrid derivatives were synthesized by connecting an inhibitor of Keap1-Nrf2 protein-protein interaction with two well-established H2S-donor moieties, respectively, via an ester linker, to find a drug candidate more effective for the UC treatment. Subsequently, the cytoprotective effects of hybrids derivatives were investigated, and DDO-1901 was identified as a candidate showing the best efficacy and used for further investigation on therapeutic effect on dextran sulfate sodium (DSS)-induced colitis in vitro and in vivo. Experimental results indicated that DDO-1901 could effectively alleviate DSS-induced colitis by improving the defense against oxidative stress and reducing inflammation, more potent than parent drugs. Compared with either drug alone, such molecular hybridization may offer an attractive strategy for the treatment of multifactorial inflammatory disease.

ARE-PROTACs Enable Co-degradation of an Nrf2-MafG Heterodimer.

Proteolysis-targeting chimera (PROTAC) technology has emerged as a potential strategy to degrade "undruggable" proteins in recent years. Nrf2, an aberrantly activated transcription factor in cancer, is generally considered undruggable as lacking active sites or allosteric pockets. Here, we constructed the chimeric molecule C2, which consists of an Nrf2-binding element and a CRBN ligand, as a first-in-class Nrf2 degrader. Surprisingly, C2 was found to selectively degrade an Nrf2-MafG heterodimer simultaneously via the ubiquitin-proteasome system. C2 impeded Nrf2-ARE transcriptional activity significantly and improved the sensitivity of NSCLC cells to ferroptosis and therapeutic drugs. The degradation character of ARE-PROTACs suggests that the PROTAC hijacking the transcription element of TFs could achieve co-degradation of the transcription complex.

Association of high-sensitivity C-reactive protein and anemia with acute kidney injury in neonates.

Background: The association of high-sensitivity C-reactive protein (hsCRP) and anemia with postoperative acute kidney injury (AKI) in neonates with congenital heart disease (CHD) is still unclear. The purpose of this study was to examine whether anemia-associated AKI is modulated by hsCRP in neonates. Methods: This study included 253 consecutive neonatal patients who underwent CHD surgery in a national tertiary hospital. We investigated the association between postoperative AKI with baseline hsCRP, anemia, and their interaction by multivariable logistic regression analyses. Results: The incidence of AKI was 24.1% in the entire cohort. After being adjusted for covariates, hsCRP level was negatively correlated with AKI (P < 0.01 for 1 mg/L threshold), whereas anemia emerged as an independent risk factor of AKI (P = 0.02). In addition, there was a significant interaction between anemia and hsCRP level (P = 0.01). In neonates with hsCRP < 1 mg/L, anemia was positively associated with AKI (P = 0.03). However, no significant association was found between anemia and AKI in the context of hsCRP ≥ 1 mg/L. Combination of anemia and hsCRP < 1 mg/L was independently correlated with the risk of AKI (P < 0.01), while concomitant anemia and hsCRP ≥ 1 mg/L or hsCRP < 1 mg/L combined with non-anemia was not. Conclusions: In neonates with CHD, the risk of anemia-associated AKI may be modulated by hsCRP level. Attention should be paid to neonates with preoperative anemia and baseline hsCRP < 1 mg/L to reduce the risk of postoperative AKI.

Non-small molecule PROTACs (NSM-PROTACs): Protein degradation kaleidoscope.

The proteolysis targeting chimeras (PROTACs) technology has been rapidly developed since its birth in 2001, attracting rapidly growing attention of scientific institutes and pharmaceutical companies. At present, a variety of small molecule PROTACs have entered the clinical trial. However, as small molecule PROTACs flourish, non-small molecule PROTACs (NSM-PROTACs) such as peptide PROTACs, nucleic acid PROTACs and antibody PROTACs have also advanced considerably over recent years, exhibiting the unique characters beyond the small molecule PROTACs. Here, we briefly introduce the types of NSM-PROTACs, describe the advantages of NSM-PROTACs, and summarize the development of NSM-PROTACs so far in detail. We hope this article could not only provide useful insights into NSM-PROTACs, but also expand the research interest of NSM-PROTACs.

Dexmedetomidine Diminishes, but Does Not Prevent, Developmental Effects of Sevoflurane in Neonatal Rats.

BACKGROUND: Sevoflurane (SEVO) increases neuronal excitation in neonatal rodent brains through alteration of gamma aminobutyric acid (GABA)(A) receptor signaling and increases corticosterone release. These actions may contribute to mechanisms that initiate the anesthetic's long-term neuroendocrine and neurobehavioral effects. Dexmedetomidine (DEX), a non-GABAergic α2-adrenergic receptor agonist, is likely to counteract SEVO-induced neuronal excitation. We investigated how DEX pretreatment may alter the neurodevelopmental effects induced by SEVO in neonatal rats. METHODS: Postnatal day (P) 5 Sprague-Dawley male rats received DEX (25 µg/kg, intraperitoneal) or vehicle before exposure to 2.1% SEVO for 6 hours (the DEX + SEVO and SEVO groups, respectively). Rats in the DEX-only group received DEX without exposure to SEVO. A subcohort of P5 rats was used for electroencephalographic and serum corticosterone measurements. The remaining rats were sequentially evaluated in the elevated plus maze on P80, prepulse inhibition of the acoustic startle response on P90, Morris water maze (MWM) starting on P100, and for corticosterone responses to physical restraint for 30 minutes on P120, followed by assessment of epigenomic DNA methylation patterns in the hippocampus. RESULTS: Acutely, DEX depressed SEVO-induced electroencephalogram-detectable seizure-like activity (mean ± SEM, SEVO versus DEX + SEVO, 33.1 ± 5.3 vs 3.9 ± 5.3 seconds, P < .001), but it exacerbated corticosterone release (SEVO versus DEX + SEVO, 169.935 ± 20.995 versus 280.853 ± 40.963 ng/mL, P = .043). DEX diminished, but did not fully abolish, SEVO-induced corticosterone responses to restraint (control: 11625.230 ± 877.513, SEVO: 19363.555 ± 751.325, DEX + SEVO: 15012.216 ± 901.706, DEX-only: 12497.051 ± 999.816; F[3,31] = 16.878, P < .001) and behavioral deficiencies (time spent in the target quadrant of the MWM: control: 31.283% ± 1.722%, SEVO: 21.888% ± 2.187%, DEX + SEVO: 28.617% ± 1.501%, DEX-only: 31.339% ± 3.087%; F[3,67] = 3.944, P = .012) in adulthood. Of the 391 differentially methylated genes in the SEVO group, 303 genes in the DEX + SEVO group had DNA methylation patterns that were not different from those in the control group (ie, they were normal). DEX alone did not cause acute or long-term functional abnormalities. CONCLUSIONS: This study suggests that the ability of DEX to depress SEVO-induced neuronal excitation, despite increasing corticosterone release, is sufficient to weaken mechanisms leading to long-term neuroendocrine/neurobehavioral abnormalities. DEX may prevent changes in DNA methylation in the majority of genes affected by SEVO, epigenetic modifications that could predict abnormalities in a wide range of functions.

Discovery of 2-((2-methylbenzyl)thio)-6-oxo-4-(3,4,5-trimethoxyphenyl)-1,6-dihydropyrimidine-5-carbonitrile as a novel and effective bromodomain and extra-terminal (BET) inhibitor for the treatment of sepsis.

Sepsis has long been a major health problem worldwide. It threatens the lives of hospitalized patients and has been one of the leading causes of death in hospitalized patients over the past decades. BRD4 has been regarded as a potential target for sepsis therapy, for its critical role in the transcriptional expression of NF-κB pathway-dependent inflammatory factors. In this study, compound 1 was obtained through virtual screening, and candidate compound 27 was obtained through several rounds of iterative SAR analysis. 27 decreased LPS-induced NO production and expression of the pro-inflammatory factors IL-6, IL-1ß and TNF-α. In vivo, 27 effectively protected mice from LPS-induced sepsis, increased survival rate and decreased the level of pro-inflammatory factors in serum. Collectively, we reported here 27, a BRD4 inhibitor with a new scaffold, as a potential candidate for the treatment of sepsis.

Investigation of myocardial protection during pediatric CPB: Practical experience in 100 Chinese hospitals.

Many measures have been proposed for myocardial protection in pediatric congenital heart surgeries, but little data is available for China. This study investigates myocardial protection strategies in pediatric cardiopulmonary bypass (CPB) throughout China. Online questionnaires were delivered to 100 hospitals in 27 provinces. The number of yearly on-pump pediatric cardiovascular surgeries in these hospitals varied greatly. About 91.0% of respondents believe that each surgery should have at least two perfusionists, while only 64.0% of hospitals actually met this requirement. For pediatric patients, crystalloid cardioplegia was more prevalent than blood-based cardioplegia. Histidine-tryptophan-ketoglutarate solution and St. Thomas crystalloid solution were dominant among crystalloid cardioplegia. Del Nido cardioplegia and St. Thomas blood-based cardioplegia ranked the top two in the popularity of blood-based cardioplegia. Dosages varied among different kinds of cardioplegia. In the choice of different cardioplegia, perfusionists mainly focused on myocardial protective effect and cost. Hypothermia of cardioplegia solution was maintained by ice buckets in 3/4 of the hospitals in this survey. In conclusion, the essence of myocardial protection management during pediatric CPB was cardiac arrest induced by cardioplegia under systemic hypothermia. However, there is no uniform standard for the type of cardioplegia, or dosages. Therefore, well-designed multicenter randomized controlled trials are warranted to provide tangible evidence for myocardial protection of cardioplegia in pediatric CPB.

The lower threshold of hypothermic oxygen delivery to prevent neonatal acute kidney injury.

BACKGROUND: Oxygen delivery during cardiopulmonary bypass (CPB) is closely related to postoperative acute kidney injury (AKI). The value of critical indexed oxygen delivery (DO2i) is a key indicator to reflect oxygen supply in cardiovascular surgery. However, the target DO2i value for neonates undergoing hypothermic CPB remains unclear. METHODS: One hundred and twenty-six consecutive newborns (≤28 days) undergoing arterial switch operations were retrospectively divided into two groups according to AKI occurrence. Baseline characteristics, intraoperative variables, and clinical outcomes were collected. Multivariate logistic regression analysis and receiver-operating characteristic curve were performed to investigate the association between DO2i and AKI. RESULTS: Neonates in the no-AKI group (n = 67) had significantly higher nadir bypass flow and DO2i during the hypothermic phase compared with the AKI group (n = 59). AKI group had remarkably higher incidences of hepatic dysfunction and peritoneal dialysis requirement compared with newborns without AKI. Mixed venous oxygen saturation (SvO2) was comparable between the two groups. Base excess (BE)(P = 0.011) value during the hypothermic phase of the AKI group was higher than the no-AKI group. Multivariate analysis showed that hypothermic DO2i was negatively associated with AKI. The cut-off value of hypothermic DO2i was 269 mL min-1 m-2. CONCLUSIONS: The importance of hypothermic DO2i should be highlighted, even when SvO2 was satisfactory. A lower threshold of DO2i > 269 mL min-1 m-2 may help protect neonates from the risk of postoperative AKI. IMPACT: The key message of our article is that the lower threshold of DO2i > 269 mL min-1 m-2 may help protect neonates from the risk of AKI after on-pump hypothermic cardiovascular surgery. The critical DO2i value for neonates undergoing hypothermic CPB remains unclear, and our study may add new evidence for this matter based on the 6-year experience of our center. In this study, the lowest critical value of DO2i in neonatal hypothermic CPB is determined for the first time, which provides a reference for intra-CPB management strategy to improve the postoperative outcomes of newborns.

Risk Factors and Long-Term Prognosis for Chylothorax After Total Cavopulmonary Connection in Children: A Retrospective Study From a Single Center.

Background: Chylothorax is a severe complication after total cavopulmonary connection (TCPC) in children. This study was performed to evaluate the incidence, risk factors, and short- and long-term prognosis for chylothorax. Methods: We retrospectively reviewed the electronic records of patients who underwent TCPC between January 2008 and December 2020 in Fuwai Hospital. Patients were divided into two groups based on the occurrence of post-operative chylothorax. Univariate and multivariate analyses were performed to identify risk factors, and long-term survival was estimated by the Kaplan-Meier method. Results: Of 386 patients included in our study, chylothorax occurred in 60 patients (15.5%). Compared with the non-chylothorax group, the prevalence of prolonged intensive care unit (ICU) stay (p = 0.000) and post-operative hospital stay (p = 0.000) were greater in patients with chylothorax. Post-operative adverse events in terms of infection (p = 0.002), ascites (p = 0.001), prolonged pleural effusion (p = 0.000), and diaphragmatic paralysis (p = 0.026) were more frequent in chylothorax patients. The median follow-up duration was 4.0 (2.0, 6.8) years. The chylothorax group had significantly lower survival rates at 1 year (92.4 vs. 99.3%, p < 0.001) and 10 years (84.6 vs. 91.6%, p < 0.001), respectively. Having a right dominant ventricle [odds ratio (OR) = 2.711, 95% confidence interval (CI) = 1.285-5.721, p = 0.009] and a higher peak central venous pressure (CVP) on post-operative day (POD) 0 (OR = 1.116, 95% CI = 1.011-1.233, p = 0.030) were the risk factors for the development of chylothorax after TCPC operation. Conclusion: The incidence of chylothorax in patients undergoing TCPC is lower than previously reported but is associated with poor early- and long-term survival. Having a right dominant ventricle and a higher peak CVP on POD 0 are the risk factors for chylothorax after TCPC operation.

Comparable prognosis in different neonatal histidine-tryptophan-ketoglutarate dosage management.

BACKGROUND: Histidine-tryptophan-ketoglutarate (HTK) is a solution commonly used for organ transplantation. However, there is no certified fixed regimen for on-pump heart surgery in neonates. We aimed to retrospectively evaluate the outcomes related to different HTK dosages and to analyze the safety of high-dosage perfusion. METHODS: A total of 146 neonates who underwent on-pump heart surgery with single-shot HTK perfusion were divided into two groups according to HTK dosages: a standard-dose (SD) group (n = 63, 40 mL/kg < HTK ≤ 60 mL/kg) and a high-dose (HD) group (n = 83, HTK >60 mL/kg). Propensity score matching (PSM) was performed to control confounding bias. RESULTS: The SD group had a higher weight (3.7 ±â€Š0.4 vs. 3.4 ±â€Š0.4 kg, P < 0.0001), a lower proportion of complete transposition of the great artery (69.8% vs. 85.5%, P = 0.022), a lower cardiopulmonary bypass (CPB) time (123.5 [108.0, 136.0] vs. 132.5 [114.8, 152.5] min, P = 0.034), and a lower aortic x-clamp time (82.9 ±â€Š27.1 vs. 95.5 ±â€Š26.0 min, P = 0.005). After PSM, 44 patients were assigned to each group; baseline characteristics and CPB parameters between the two groups were comparable. There were no significant differences in peri-CPB blood product consumption after PSM (P > 0.05). The incidences of post-operative complications were not significantly different between the two groups. There were no significant differences in ventilation time, intensive care unit stay, and post-operative hospital stay (P > 0.05). Follow-up echocardiography outcomes at 1 month, 3 to 6 months, and 1 year showed that left ventricular ejection fraction and end-diastolic dimension were comparable between the two groups. CONCLUSIONS: In neonatal on-pump cardiac surgery patients, single-shot HD (>60 mL/kg) HTK perfusion had a comparable heart protection effect and short-term post-operative prognosis as standard dosage perfusion of 40 to 60 mL/kg. Thus, this study provides supporting evidence of the safety of HD HTK perfusion.

Discovery of 3,5-Dimethyl-4-Sulfonyl-1H-Pyrrole-Based Myeloid Cell Leukemia 1 Inhibitors with High Affinity, Selectivity, and Oral Bioavailability.

Myeloid cell leukemia 1 (Mcl-1) protein is a key negative regulator of apoptosis, and developing Mcl-1 inhibitors has been an attractive strategy for cancer therapy. Herein, we describe the rational design, synthesis, and structure-activity relationship study of 3,5-dimethyl-4-sulfonyl-1H-pyrrole-based compounds as Mcl-1 inhibitors. Stepwise optimizations of hit compound 11 with primary Mcl-1 inhibition (52%@30 µM) led to the discovery of the most potent compound 40 with high affinity (Kd = 0.23 nM) and superior selectivity over other Bcl-2 family proteins (>40,000 folds). Mechanistic studies revealed that 40 could activate the apoptosis signal pathway in an Mcl-1-dependent manner. 40 exhibited favorable physicochemical properties and pharmacokinetic profiles (F% = 41.3%). Furthermore, oral administration of 40 was well tolerated to effectively inhibit tumor growth (T/C = 37.3%) in MV4-11 xenograft models. Collectively, these findings implicate that compound 40 is a promising antitumor agent that deserves further preclinical evaluations.

A Monocyte-Orchestrated IFN-I-to-IL-4 Cytokine Axis Instigates Protumoral Macrophages and Thwarts Poly(I:C) Therapy.

Type I IFNs (IFN-I) are important for tumor immune surveillance and contribute to the therapeutic responses for numerous treatment regimens. Nevertheless, certain protumoral activities by IFN-I have been increasingly recognized. Indeed, our recent work showed that systemic poly(I:C)/IFN treatment can undesirably trigger high arginase (ARG1) expression within the tumor-associated monocyte/macrophage compartment. Using a line of CRISPR-generated Arg1-YFP reporter knock-in mice, we have determined that a subset of tumor-associated macrophages represent the major Arg1-expressing cell type following poly(I:C)/IFN stimulation. More detailed analyses from in vitro and in vivo models demonstrate a surprising IFN-to-IL-4 cytokine axis in transitional monocytes, which can subsequently stimulate IL-4 target genes, including Arg1, in macrophages. Intriguingly, IFN stimulation of transitional monocytes yielded concurrent M2 (YFP+)- and M1 (YFP-)-skewed macrophage subsets, correlated with an inhibitory crosstalk between IFN-I and IL-4. Genetic abrogation of IL-4 signaling in mice diminished poly(I:C)/IFN-induced ARG1 in tumors, leading to enhanced activation of CD8+ T cells and an improved therapeutic effect. The present work uncovered a monocyte-orchestrated macrophage phenotype conversion mechanism that may have broad implications.

Discovery of a covalent inhibitor of heat shock protein 90 with antitumor activity that blocks the co-chaperone binding via C-terminal modification.

Heat shock protein (Hsp90), a critical molecular chaperone that regulates the maturation of a large number of oncogenic client proteins, plays an essential role in the growth of neoplastic cells. Herein, DDO-6600 is identified to covalent modification of Cys598 on Hsp90 from in silico study and is verified by a series of biological assays. We demonstrated that DDO-6600 covalently bound to Cys598 on the Hsp90 C terminus and exhibited antiproliferative activities against multiple tumor cells without inhibiting ATPase activity. Further studies showed that DDO-6600 disrupted the interaction between Hsp90 and Cdc37, which induced the degradation of kinase client proteins in multiple tumor cell lines, promoted apoptosis, and inhibited cell motility. Our findings offer mechanic insights into the covalent modification of Hsp90 and provide an alternative strategy for the development of Hsp90 covalent regulators or chemical probes to explore the therapeutical potential of Hsp90.

Contrast media exposure in the perioperative period confers no additional risk of acute kidney injury in infants and young children undergoing cardiac surgery with cardiopulmonary bypass.

BACKGROUND: Recently, there has been an interest in the temporal relationship between contrast exposure (CM) and cardiac surgery suggesting that a "double hit" on the kidney function in close succession increases the risk of acute kidney injury (AKI) after cardiac surgery. However, data from young children is limited. The purpose of this study was to retrospectively evaluate the effects of preoperative CM exposure on postoperative AKI in infant and young children patients and to further analyze the influence of exposure time interval. METHODS: Patients (age ≤ 3 years) who underwent diagnostic imaging within 14 days before on-pump cardiac surgery between 1 May 2017 and 31 May 2018 in Fuwai Hospital, Beijing, were analyzed. Kidney outcome was assessed according to Kidney Disease: Improving Global Outcomes creatinine-based criteria. RESULTS: One thousand four hundred pediatric patients (192 CM and 1,248 non-CM) were identified. Postoperative AKI occurred in 57 (29.7%) of the 192 patients who were exposed to CM. Following propensity score adjustment, no difference in risk for AKI was observed between the CM and non-CM groups (RR 1.142, 95% CI 0.916-1.424; P = 0.264). Multivariable logistic regression of the CM group indicated that independent predictors of postoperative AKI were lower weight, lower preoperative creatinine level, and longer CPB duration. Time interval between CM exposure and on-pump cardiac surgery was not significantly associated with increased risk of AKI (OR 0.853, 95% CI 0.265~2.747; P = 0.790). CONCLUSIONS: For pediatric patients who are soon to undergo on-pump cardiac procedures, there appears to be no need to hesitate in performing the diagnostic imaging investigations requiring CM, or delay CPB after CM exposure. These patients may benefit from increased diagnostic utility without increasing their risk of postoperative AKI.