Efficacy and safety of adamgammadex for reversing rocuronium-induced deep neuromuscular blockade: A multicenter, randomized, phase IIb study.

The rapid reversal of deep neuromuscular blockade (NMB) is important but remains challenging. This study aimed to evaluate the efficacy and safety of adamgammadex versus sugammadex in reversing deep rocuronium-induced NMB. This multicenter, randomized, phase IIb study included 80 patients aged 18-64 years, American Society of Anesthesiologists (ASA) grade 1-2, undergoing elective surgery under general anesthesia with rocuronium. Patients were randomized to the adamgammadex 7, 8, and 9 mg/kg group or the sugammadex 4 mg/kg group. The primary efficacy variable was the time to recovery of train-of-four ratio (TOFr) to 0.9. The secondary efficacy variables were the time to recovery of TOFr to 0.7, antagonistic success rate of the recovery of TOFr to 0.9 within 5 min, and incidence rate of recurarization within 30 min after drug administration. The explorative efficacy variable was the time to recovery of the corrected TOFr to 0.9 (actual/baseline TOF ratio). Adamgammadex 7, 8, and 9 mg/kg and sugammadex 4 mg/kg groups did not significantly differ in all efficacy variables. Importantly, adamgammadex 9 mg/kg permitted reversal within a geometric mean of 2.9 min. According to the safety profile, adamgammadex achieved good tolerance and low incidence of drug-related adverse events compared with the 4 mg/kg sugammadex. Adamgammadex 7, 8, and 9 mg/kg facilitated rapid reversal of deep rocuronium-induced NMB and had good tolerance and low incidence of drug-related adverse events. Therefore, adamgammadex is a potential and promising alternative to sugammadex.

Evaluation of a concise fall risk stratification among older adults with cataracts in day surgery settings: A historically controlled study.

AIM: This study aimed to evaluate the use of a concise fall risk stratification in assessing and predicting falls compared with the Morse Falls Scale among older adults with cataracts in day surgery settings. METHODS: A historically controlled study conducted from July 2020 to June 2022 was used in a municipal ophthalmic hospital in China. The concise fall risk stratification which directly graded fall risk by multifactorial judgment was used during the intervention period, while the Morse Falls Scale which graded fall risk by scale scores was used during the control period. The fall risk levels, fall assessment time, fall rates, fall-related injuries, predictive validity, and patient satisfaction with day surgery care were extracted. Propensity score matching was performed to balance baselines. RESULTS: After matching, 4132 patients were included in the final analysis. Compared with the control group, the intervention group had significantly higher assessment results for fall risk level, a significantly shorter (by 48.15%) fall assessment time, and higher patient satisfaction. There were no differences in fall rates and fall-related injuries. Compared with the Morse Falls Scale, the concise fall risk stratification had higher sensitivity and negative predictive validity, and lower specificity and positive predictive validity, while the area under curve did not differ significantly. CONCLUSION: The use of the concise fall risk stratification reduced fall assessment time, improved patient satisfaction, and is unlikely to impact falls with an overall predictive performance comparable to that of the Morse Falls Scale for older cataract adults in day surgery settings.

Termination of a second-trimester pregnancy with placenta accreta spectrum disorder.

Background: The termination of pregnancy in patients with placenta accreta spectrum disorder (PASD) during the second trimester remains uncertain. In addition, interventional radiology techniques, such as arterial embolization and balloon placement, are potential options. We evaluated the outcomes of pregnancy termination in patients with PASD during the second trimester and the effectiveness of preoperative interventional radiology techniques.Methods: This retrospective study analyzed 48 PASD patients who underwent pregnancy termination during the second trimester between January 2016 and May 2021.Results: Of the 48 patients, 20 (41.67%) underwent transvaginal termination, whereas 28 (58.33%) underwent cesarean section. Notably, no significant differences were observed in success rates between the transvaginal termination and cesarean section groups (80.00% vs. 92.86%, P = 0.38). Furthermore, no statistically significant differences were observed in the success rates (94.12% vs 90.32%, P = 1.00) and blood loss (512.35 ± 727.00 ml vs 804.00 ± 838.98 ml, P = 0.23) between the artery embolization and non-embolization groups. In the vaginal termination group, statistically significant differences were observed in gestational weeks (16.70 ± 3.12 vs 22.67 ± 3.63, P < 0.01) and blood loss (165.00 ± 274.43 ml vs 483.64 ± 333.53 ml, P = 0.04) between the (artery embolization and non-embolization) subgroups. Conversely, in the cesarean section group, no significant differences were observed in gestational weeks (23.59 ± 3.14 vs 23.20 ± 4.37, P = 0.79) and blood loss (811.11 ± 879.55 ml vs 989.47 ± 986.52 ml, P = 0.76) between the subgroups.Conclusions: Further studies are needed to evaluate the efficacy of vaginal termination in PASD patients during the second trimester. Regarding cesarean termination, arterial embolization did not demonstrate increased effectiveness.

A novel pathogenic deletion in ISPD causes Walker-Warburg syndrome in a Chinese family.

BACKGROUND: Walker-Warburg syndrome (WWS) is a genetically heterogeneous disease that often presents with complex brain and eye malformations and congenital muscular dystrophy. Mutations of the ISPD gene have been identified as one of the most frequent causes of WWS. OBJECTIVE: The current study aimed to identify the cause of severe congenital hydrocephalus and brain dysplasia in our subject. METHODS: Genomic DNA was extracted from the fetus's umbilical cord blood and peripheral venous blood of the parents. The genetic analysis included whole-exome sequencing and qPCR. Additionally, in silico analysis and cellular experiments were performed. RESULTS: We identified a novel homozygous deletion of exons 7 to 9 in the ISPD gene of the fetus with WWS. In silico analysis revealed a defective domain structure in the C-terminus domain of the ISPD. Analysis of the electrostatic potential energy showed the formation of a new binding pocket formation on the surface of the mutant ISPD gene (ISPD-del ex7-9). Cellular study of the mutant ISPD revealed a significant change in its cellular localization, with the ISPD-del ex7-9 protein translocating from the cytoplasm to the nucleus compared to wild-type ISPD, which is mostly present in the cytoplasm. CONCLUSION: The present study expands the mutational spectrum of WWS caused by ISPD mutations. Importantly, our work suggests that whole-exome sequencing could be considered as a diagnostic option for fetuses with congenital hydrocephalus and brain malformations when karyotype or chromosomal microarray analysis fails to provide a definitive diagnosis.

The early function of cortisol in liver during Aeromonas hydrophila infection: Dynamics of the transcriptome and accessible chromatin landscapes.

In China, channel catfish (Ictalurus punctatus) is an important aquaculture species; however, haemorrhagic disease (Aeromonas hydrophila induced disease) in these fish has caused tremendous economic loss due to high morbidity and mass mortality in the breeding industry. The role of cortisol in bacterial diseases, particularly in the acute phase, remains unclear. In this study, liver transcriptome (RNA-seq) and chromatin accessibility (ATAC-seq) analyses were employed to investigate the early functional role of cortisol in Aeromonas hydrophila-stimulated responses. Our experiments confirmed that A. hydrophila infection can initially significantly increase serum cortisol levels at 1 h after infection. At this time point, the increased serum cortisol levels can significantly regulate A. hydrophila-regulated genes by affecting both transcriptome and chromatin accessibility. Cross-analysis of RNA-seq and ATAC-seq revealed that a certain gene group (92 target_DEGs) was regulated at an early time point by cortisol. KEGG enrichment analysis revealed that the top three pathways according to target_DEGs were cancer, glutathione metabolism, and the Notch signalling pathway. The protein-protein interaction analysis of target_DEGs revealed that they may be primarily involved in cell proliferation, CD8+ T cell function, glutathione synthesis, and activation of the NF-κB signalling pathway. This suggests that after the emergence of immune stress, the early regulation of cortisol is positive against the immune response. It is possible that in this situation, the animal is attempting to avoid dangerous situations and risks and then cope with the imbalance produced by the stressor to ultimately restore homeostasis. Our results will contribute to future research on fish and provide valuable insight regarding the mechanism of immune regulation by cortisol and the study of bacterial haemorrhagic disease in channel catfish.

The impact of tubeless anesthesia versus intubated anesthesia on cerebral oxygen saturation and postoperative cognitive function in patients undergoing video-assisted thoracoscopic surgery: a randomized trial.

Background: In video-assisted thoracoscopic surgery (VATS), intubated anesthesia may affect cerebral oxygen balance and postoperative cognitive dysfunction (POCD). To avoid complications associated with intubated anesthesia, tubeless strategies have been proposed in recent years, but its effect on cerebral oxygen balance and POCD is still unclear. This prospective study compared the cerebral oxygen saturation and the incidence of POCD in patients undergoing VATS anesthetized with tubeless anesthesia vs. intubated anesthesia. Methods: A total of 60 patients with American Society of Anesthesiologists Standard (ASA) grade I-II who planned to undergo VATS at The First People's Hospital of Yunnan Province between May and October 2021 were selected and divided into non-intubated spontaneous ventilation group (SV group) or intubated mechanical ventilation group (MV group) by random number method. The primary outcome included the incidence of POCD and Mini-Mental State Examination (MMSE) on the 1st before operation and the 4th, 7th, 14th, and 30th day postoperatively, and cerebral oxygen saturation during surgery. Other outcomes of interest include respiratory and hemodynamic parameters, serum concentration of cognitive function related proteins [S100ß, interleukin (IL)-6, IL-1ß, and tumor necrosis factor α (TNF-α)], inflammatory cell counts, perioperative adverse events (arrhythmia, hypoxemia, asphyxia, etc.), postoperative pain scores, etc. Results: The incidence of hypercapnia in the SV group was significantly higher than in the MV group (P<0.001). Cerebral oxygen saturation at intraoperative was significantly higher than that in MV group (P<0.01). There was no significant difference in the incidence of POCD and the expression of cognitive function related proteins between the two groups (P>0.05). Leukocyte and neutrophil counts were significantly higher in the MV group after operation (P<0.05), whilst compared to the MV group, the SV group showed shorter postoperative recovery time, rest time before the first out of bed activity, chest tube duration, as well as less drainage volume of the chest tube and postoperative sore throat rarely occurred (P<0.05). Conclusions: Tubeless VATS can increase the incidence of hypercapnia and intraoperative cerebral oxygen saturation, but has no statistically significant difference in the incidence of POCD. In addition, tubeless anesthesia reduces systemic inflammatory, promotes the early postoperative mobilization, and accelerates the postoperative rehabilitation of patients. Trial Registration: Chinese Clinical Trial Registry ChiCTR2100042381.

Nalbuphine 20 mg combined with sufentanil 2 µg/kg exerts a better postoperative analgesia effect in patients undergoing a second cesarean section: a randomised trial.

BACKGROUND: Pain management following cesarean section remains a challenge, with many puerpera suffering from severe acute postoperative pain. And for a second cesarean section the degree of uterine contraction pain is more severe and frequent than that of a primipara. This study investigated the effect of different doses of nalbuphine combined with sufentanil for postoperative analgesia in patients undergoing a second cesarean section. METHODS: We prospectively recruited 168 women with a scarred uterus undergoing elective second cesarean section and they were randomly divided into 4 groups by random number extraction. A single intravenous injection of different doses of nalbuphine was given before the intravenous drip of oxytocin, and visual analogue scale (VAS) scores of uterine contraction pain were recorded 10 minutes before intravenous infusion of oxytocin (T1) and 10 minutes (T2), 30 minutes (T3), and 60 minutes (T4) after intravenous infusion of oxytocin. At 4, 8, 12, 24, and 48 hours after patient-controlled intravenous analgesia (PCIA), pain intensity was reassessed using the VAS score. RESULTS: One hundred and sixty patients underwent elective second cesarean section in between December 2020 and May 2021 completed the study. The VAS scores of uterine contractions at T1 and T4 were 3 (1.0), while the VAS scores at T2 and T3 were 7 (1.0), 6 (1.0), 5 (1.0), 5 (1.0) and 8 (1.0), 5 (2.0), 3 (1.0), 3 (0.75). The VAS scores at 12 hours after surgery of nalbuphine10mg and sufentanil (NS1), nalbuphine 10 mg and sufentanil 20 mg (NS2) and nalbuphine 30 mg and sufentanil 20 mg (NS3) were lower than sufentanil (S) group (P<0.001). Compared with the S group, total amount of sufentanil and PCIA compression numbers in the NS1, NS2, and NS3 groups at 4-8 and 8-12 hours after surgery decreased (P<0.001), with a more significant decrease in the NS2 and NS3 groups than in the NS1 group (P<0.001). The NS3 group had a significantly higher incidence of dizziness and sleepiness (P=0.02, P=0.001). Compared with the NS2 and NS3 groups, the incidence of respiratory depression in the S group was significantly higher (P=0.001). CONCLUSIONS: A single intravenous injection of nalbuphine 20 mg 10 minutes before the infusion of oxytocin combined with sufentanil 2 µg/kg could be safely used for postoperative analgesia in patients undergoing a second cesarean section and could effectively inhibit uterine contractions induced by oxytocin and reduce adverse reactions. TRIAL REGISTRATION: Clinical Trial Registry ChiCTR2100042382.

Atractylodin alleviates cancer anorexia-cachexia syndrome by regulating NPY through hypothalamic Sirt1/AMPK axis-induced autophagy.

Cancer anorexia-cachexia syndrome (CACS) is a complex syndrome associated with loss of muscle and adipose tissue and weight loss, and is a major lethal factor in the later stages of cancer. The mechanism of action of CACS is not fully understood and there are no drugs specifically approved for its treatment. Atractylodin, the main active component of Atractylodes lancea, is widely used in the treatment of digestive disorders and has the ability to reduce IL-1, IL-6 and TNF-α levels. Our results showed that gavage with Atractylodin increased body weight, muscle and fat weight and reduced tumor weight and volume as well as abnormally high serum concentrations of the muscle atrophy-causing cytokines IL-1ß, IL-6 and TNF-α in CACS model mice. RT-PCR data revealed that Atractylodin promoted the expression of the pro-feeding NPY and suppressed the expression of the anorexia POMC in the hypothalamus. Western blot results showed that Atractylodin promoted the expression of Sirt1 and p-AMPK in the hypothalamus, accompanied by an increase in autophagy. Furthermore, the Sirt1 inhibitor EX527 or AMPK inhibitor Compound C (CC) reversed Atractylodin-induced beneficial effects in CACS model mice. In hypothalamic cells subjected to glucose deprivation, Atractylodin increased NPY mRNA expression by enhancing AMPK-modulated autophagy; while EX527 or Compound C blunted Atractylodin-induced autophagy enhancement effect in vitro. In conclusion, Atractylodin can be used as an anti-cachexia drug and the underlying mechanism may involve the promotion of NPY expression by Sirt1/AMPK-regulated autophagy.

OGG1 contributes to hepatocellular carcinoma by promoting cell cycle-related protein expression and enhancing DNA oxidative damage repair in tumor cells.

BACKGROUND: This study aimed to analyze the expression of 8-oxoguanine DNA glycosylase (OGG1) in patients with hepatocellular carcinoma (HCC) and its effect on prognosis by bioinformatics techniques and to determine its possible carcinogenic mechanism through data mining. METHODS: The difference in OGG1 expression between healthy people and HCC patients was searched and analyzed by TCGA and GEO databases, and the effect of OGG1 on prognosis was judged by survival analysis. Meanwhile, the possible molecular mechanism of OGG1 in the tumorigenesis and development of HCC was explored by GO analysis, KEGG analysis, immune infiltration analysis, protein-protein interaction network, promoter methylation analysis, and so forth. Quantitative polymerase chain reaction (qPCR) was used to examine the gene expression in 36 pairs of HCC tissues and adjacent tissues. RESULTS: The expression of OGG1 in HCC patients was higher than that in healthy people, and the overexpression of OGG1 might stimulate cell proliferation by increasing the activity of cell cycle-related proteins. CONCLUSION: The alteration of OGG1 was significantly correlated with the tumorigenesis and development of HCC. OGG1 is expected to be a new biomarker for evaluating the prognosis of HCC and a new target for the treatment of HCC.

Effect of Lanthanum Oxide Addition on Microstructure and Wear Performance of Iron-Chromium Alloy Manufactured by Laser Direct Deposition Additive Manufacturing.

Additive Manufacturing (AM) has become increasingly common, and its use in various industries is increasing. However, the microstructure, friction and wear performance of metals made by AM, such as the inexpensive and relatively good-performing iron-chromium alloys, require further investigation. Generally, adding rare earth elements can effectively improve the performance of AM alloys, such as tensile strength, wear resistance, corrosion resistance, creep resistance, etc. This work aims to study the variation of microstructure, friction and wear properties of laser additive manufacturing processed iron-chromium alloys after adding different mass fractions of La2O3. The observations obtained by scanning electron microscopy showed that, with the addition of La2O3, the microstructure of AM alloy becomes more uniform and the grains are significantly refined. It is found by friction test that the running-in period is significantly shortened after the addition of La2O3. The coefficient of friction is reduced to a minimum of 0.68. Compared with AM alloys without La2O3, the wear rate of AM alloys with La2O3 is significantly reduced, with a maximum reduction of 38%. Using an optical microscope to observe the surface morphology of the wear scar, it is found that, after adding rare earth oxide, the wear mechanisms changed from adhesive wear and abrasive wear to abrasive wear, with the spalling of hard particles at the same time.

Loss of MAT2A compromises methionine metabolism and represents a vulnerability in H3K27M mutant glioma by modulating the epigenome.

Diffuse midline gliomas (DMGs) bearing driver mutations of histone 3 lysine 27 (H3K27M) are incurable brain tumors with unique epigenomes. Here, we generated a syngeneic H3K27M mouse model to study the amino acid metabolic dependencies of these tumors. H3K27M mutant cells were highly dependent on methionine. Interrogating the methionine cycle dependency through a short-interfering RNA screen identified the enzyme methionine adenosyltransferase 2A (MAT2A) as a critical vulnerability in these tumors. This vulnerability was not mediated through the canonical mechanism of MTAP deletion; instead, DMG cells have lower levels of MAT2A protein, which is mediated by negative feedback induced by the metabolite decarboxylated S-adenosyl methionine. Depletion of residual MAT2A induces global depletion of H3K36me3, a chromatin mark of transcriptional elongation perturbing oncogenic and developmental transcriptional programs. Moreover, methionine-restricted diets extended survival in multiple models of DMG in vivo. Collectively, our results suggest that MAT2A presents an exploitable therapeutic vulnerability in H3K27M gliomas.

RDAU-Net: Based on a Residual Convolutional Neural Network With DFP and CBAM for Brain Tumor Segmentation.

Due to the high heterogeneity of brain tumors, automatic segmentation of brain tumors remains a challenging task. In this paper, we propose RDAU-Net by adding dilated feature pyramid blocks with 3D CBAM blocks and inserting 3D CBAM blocks after skip-connection layers. Moreover, a CBAM with channel attention and spatial attention facilitates the combination of more expressive feature information, thereby leading to more efficient extraction of contextual information from images of various scales. The performance was evaluated on the Multimodal Brain Tumor Segmentation (BraTS) challenge data. Experimental results show that RDAU-Net achieves state-of-the-art performance. The Dice coefficient for WT on the BraTS 2019 dataset exceeded the baseline value by 9.2%.

The preventive effects of aspirin on preeclampsia based on network pharmacology and bioinformatics.

This study aimed to reveal the key targets and molecular mechanisms of aspirin in preventing preeclampsia. We used bioinformatics databases to collect the candidate targets for aspirin and preeclampsia. The biological functions and signaling pathways of the intersecting targets were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Then, the hub targets were identified by cytoscape plugin cytoHubba from the protein-protein interaction network. We collected 90 targets for aspirin in preventing preeclampsia. The biological processes of the intersecting targets are mainly involved in xenobiotic metabolic process, inflammatory response, negative regulation of apoptotic process, and protein phosphorylation. The highly enriched pathways were FoxO signaling pathway, circadian rhythm, insulin resistance, arachidonic acid metabolism, and drug metabolism-cytochrome P450. The hub targets for aspirin in preventing preeclampsia were tumor protein p53 (TP53), C-X-C motif chemokine ligand 8 (CXCL8), mitogen-activated protein kinase 3 (MAPK3), mitogen-activated protein kinase 1 (MAPK1), mitogen-activated protein kinase 14 (MAPK14), epidermal growth factor receptor (EGFR), estrogen receptor (ESR1), and prostaglandin-endoperoxide synthase 2 (PTGS2). Molecular docking results showed good bindings between the proteins and aspirin. In conclusion, these findings highlight the key targets and molecular mechanisms of aspirin in preventing preeclampsia.

The Preventive Effects of Quercetin on Preterm Birth Based on Network Pharmacology and Bioinformatics.

Our previous study has shown that quercetin prevented lipopolysaccharide-induced preterm birth. This study aims to clarify the potential targets and biological mechanisms of quercetin in preventing preterm birth. We used bioinformatics databases to collect the candidate targets for quercetin and preterm birth. The biological functions and enriched pathways of the intersecting targets were analyzed by gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. Then, the hub targets were identified by cytoscape plugin cytoHubba from the protein-protein interaction network. We obtained 105 targets for quercetin in preventing preterm birth. The biological processes of the intersecting targets are mainly involved in steroid metabolic process, drug metabolic process, oxidation-reduction process, omega-hydroxylase P450 pathway, positive regulation of cell migration, negative regulation of apoptotic process, and positive regulation of cell proliferation. The highly enriched pathways were steroid hormone biosynthesis, metabolism of xenobiotics by cytochrome P450, proteoglycans in cancer, focal adhesion, and arachidonic acid metabolism. The ten hub targets for quercetin in preventing preterm birth were AKT serine/threonine kinase 1, mitogen-activated protein kinase 3, epidermal growth factor receptor, prostaglandin-endoperoxide synthase 2, mitogen-activated protein kinase 1, estrogen receptor 1, heat shock protein 90 alpha family class A member 1, mitogen-activated protein kinase 8, androgen receptor, and matrix metallopeptidase 9. Molecular docking analysis showed good bindings between these proteins and quercetin. In conclusion, these findings highlight the key targets and molecular mechanisms of quercetin in preventing preterm birth.

Placenta Accreta Spectrum Outcomes Using Tourniquet and Forceps for Vascular Control.

Objective: To evaluate the use of tourniquet and forceps to reduce bleeding during surgical treatment of severe placenta accreta spectrum (placenta increta and placenta percreta). Methods: A tourniquet was used in the lower part of the uterus during surgical treatment of severe placenta accreta spectrum. Severe placenta accreta spectrum was classified into two types according to the relative position of the placenta and tourniquet during surgery: upper-tourniquet type, in which the entire placenta was above the tourniquet, and lower-tourniquet type, in which part or all of the placenta was below the tourniquet. The surgical effects of the two types were retrospectively compared. We then added forceps to the lower-tourniquet group to achieve further bleeding reduction. Finally, the surgical effects of the two types were prospectively compared. Results: During the retrospective phase, patients in the lower-tourniquet group experienced more severe symptoms than did patients in the upper-tourniquet group, based on mean intraoperative blood loss (upper-tourniquet group 787.5 ml, lower-tourniquet group 1434.4 ml) intensive care unit admission rate (upper-tourniquet group 1.0%, lower-tourniquet group 33.3%), and length of hospital stay (upper-tourniquet group 10.2d, lower-tourniquet group 12.1d). During the prospective phase, after introduction of the revised surgical method involving forceps (in the lower-tourniquet group), the lower-tourniquet group exhibited improvements in the above indicators (intraoperative average blood loss 722.9 ml, intensive care unit admission rate 4.3%, hospital stays 9.0d). No increase in the rate of complications was observed. Conclusion: The relative positions of the placenta and tourniquet may influence the perioperative risk of severe placenta accreta spectrum. The method using a tourniquet (and forceps if necessary) can improve the surgical effect in cases of severe placenta accreta spectrum.

Efficiency and Safety of the Selective Relaxant Binding Agent Adamgammadex Sodium for Reversing Rocuronium-Induced Deep Neuromuscular Block: A Single-Center, Open-Label, Dose-Finding, and Phase IIa Study.

Background: Rapid reversal of neuromuscular block after surgery and anesthesia is often necessary. Here, we reported the primary efficacy and safety data from a phase IIa study on adamgammadex sodium, a newly developed modified γ-cyclodextrin derivative. Methods: This was a phase IIa, single-center, randomized, open-label, and dose-finding study that enrolled 35 patients under general anesthesia who received the neuromuscular blocking agent rocuronium for induction and maintenance of neuromuscular blockade. The subjects were randomized to one of the five adamgammadex dose groups (2, 4, 6, 8, and 10 mg kg-1) and to the 4 mg kg-1 sugammadex group. Pharmacological efficacy was the recovery time from the start of adamgammadex or sugammadex administration to train-of-four (TOF) ratio ≥0.9, 0.8, and 0.7 among the different dose groups. Adverse events were recorded throughout the study. Results: The efficacy in reversing deep neuromuscular block was the same between 4 mg kg-1 sugammadex and adamgammadex. However, in the lowest dose groups of 2 and 4 mg kg-1 adamgammadex, adequate reversal could not be achieved in all subjects. The recovery time of TOF ratio to 0.9, 0.8, and 0.7 was shorter in the adamgammadex 10 mg kg-1 group than in the sugammadex 4 mg kg-1 group. The average values of the TOF ratio after 3 min of administration of adamgammadex 8 and 10 mg kg-1 and sugammadex 4 mg kg-1 were >90%. There were no serious adverse events after the use of adamgammadex, and no subjects had to be withdrawn from the trial. Conclusions: Adamgammadex enabled quick, predictable, and tolerable reversion of rocuronium-induced deep neuromuscular block in a dose-dependent manner. Adamgammadex doses of 6-10 mg kg-1 might be the recommended dose range for further exploration of efficacy. Clinical Trial Registration: This study was registered at chictr.org.cn, identifier: ChiCTR2000038391.

DFP-ResUNet:Convolutional Neural Network with a Dilated Convolutional Feature Pyramid for Multimodal Brain Tumor Segmentation.

BACKGROUND AND OBJECTIVE: Manual brain tumor segmentation by radiologists is time consuming and subjective. Therefore, fully automatic segmentation of different brain tumor subregions is essential to the treatment of patients. In this paper, we propose a neural network for automatically segmenting the enhancing tumor (ET), whole tumor (WT), and tumor core (TC) brain tumor subregions. METHODS: The network is based on a U-Net with encoding and decoding structure, a residual module, and a spatial dilated feature pyramid (DFP) module, namely, DFP-ResUNet. First, we propose using a spatial DFP module composed of multiple parallel dilated convolution layers to extract the multiscale image features. This spatial DFP structure improves the ability of the neural network to extract and utilize the multiscale image features. Then, we use the residual module to deepen the network structure. Further, we propose using a multiclass Dice loss function to suppress the impact of class imbalance on brain tumor segmentation. We carried out a large number of ablation experiments to verify the feasibility and superiority of our approach using the Multimodal Brain Tumor Segmentation (BraTS) challenge dataset. RESULTS: The mean Dice score of different subregions was ET 0.8431, WT 0.897 and TC 0.9068 using the proposed method on the BraTS 2018 challenge validation set and 0.7985, 0.90281, 0.8453 on the BraTS 2019 challenge, respectively. Further, we got a high Sensitivity and Specificity and low Hausdorff distance. CONCLUSIONS: Through the analysis of the experimental results, it can be seen that the proposed approach DFP-ResUNet has a great potential in segmenting different subregions of brain tumors and can be applied in clinical practice.

Single-PanIN-seq unveils that ARID1A deficiency promotes pancreatic tumorigenesis by attenuating KRAS-induced senescence.

ARID1A is one of the most frequently mutated epigenetic regulators in a wide spectrum of cancers. Recent studies have shown that ARID1A deficiency induces global changes in the epigenetic landscape of enhancers and promoters. These broad and complex effects make it challenging to identify the driving mechanisms of ARID1A deficiency in promoting cancer progression. Here, we identified the anti-senescence effect of Arid1a deficiency in the progression of pancreatic intraepithelial neoplasia (PanIN) by profiling the transcriptome of individual PanINs in a mouse model. In a human cell line model, we found that ARID1A deficiency upregulates the expression of aldehyde dehydrogenase 1 family member A1 (ALDH1A1), which plays an essential role in attenuating the senescence induced by oncogenic KRAS through scavenging reactive oxygen species. As a subunit of the SWI/SNF chromatin remodeling complex, our ATAC sequencing data showed that ARID1A deficiency increases the accessibility of the enhancer region of ALDH1A1. This study provides the first evidence that ARID1A deficiency promotes pancreatic tumorigenesis by attenuating KRAS-induced senescence through the upregulation of ALDH1A1 expression.

ZFTA Translocations Constitute Ependymoma Chromatin Remodeling and Transcription Factors.

ZFTA (C11orf95)-a gene of unknown function-partners with a variety of transcriptional coactivators in translocations that drive supratentorial ependymoma, a frequently lethal brain tumor. Understanding the function of ZFTA is key to developing therapies that inhibit these fusion proteins. Here, using a combination of transcriptomics, chromatin immunoprecipitation sequencing, and proteomics, we interrogated a series of deletion-mutant genes to identify a tripartite transformation mechanism of ZFTA-containing fusions, including: spontaneous nuclear translocation, extensive chromatin binding, and SWI/SNF, SAGA, and NuA4/Tip60 HAT chromatin modifier complex recruitment. Thereby, ZFTA tethers fusion proteins across the genome, modifying chromatin to an active state and enabling its partner transcriptional coactivators to promote promiscuous expression of a transforming transcriptome. Using mouse models, we validate further those elements of ZFTA-fusion proteins that are critical for transformation-including ZFTA zinc fingers and partner gene transactivation domains-thereby unmasking vulnerabilities for therapeutic targeting. SIGNIFICANCE: Ependymomas are hard-to-treat brain tumors driven by translocations between ZFTA and a variety of transcriptional coactivators. We dissect the transforming mechanism of these fusion proteins and identify protein domains indispensable for tumorigenesis, thereby providing insights into the molecular basis of ependymoma tumorigenesis and vulnerabilities for therapeutic targeting.This article is highlighted in the In This Issue feature, p. 2113.