The development and validation of automated machine learning models for predicting lymph node metastasis in Siewert type II T1 adenocarcinoma of the esophagogastric junction.

Background: Lymph node metastasis (LNM) is considered an essential prognosis factor for adenocarcinoma of the esophagogastric junction (AEG), which also affects the treatment strategies of AEG. We aimed to evaluate automated machine learning (AutoML) algorithms for predicting LNM in Siewert type II T1 AEG. Methods: A total of 878 patients with Siewert type II T1 AEG were selected from the Surveillance, Epidemiology, and End Results (SEER) database to develop the LNM predictive models. The patients from two hospitals in Suzhou were collected as the test set. We applied five machine learning algorithms to develop the LNM prediction models. The performance of predictive models was assessed using various metrics including accuracy, sensitivity, specificity, the area under the curve (AUC), and receiver operating characteristic (ROC) curve. Results: Patients with LNM exhibited a higher proportion of male individuals, a poor degree of differentiation, and submucosal infiltration, with statistical differences. The deep learning (DL) model demonstrated relatively good accuracy (0.713) and sensitivity (0.868) among the five models. Moreover, the DL model achieved the highest AUC (0.781) and sensitivity (1.000) in the test set. Conclusion: The DL model showed good predictive performance among five AutoML models, indicating the advantage of AutoML in modeling LNM prediction in patients with Siewert type II T1 AEG.

Comparative analysis of robotically-assisted versus conventional sternotomy approach in left atrial myxoma resection: A single-center retrospective observational study.

BACKGROUND: Minimally invasive surgery has emerged as a favorable alternative to conventional surgery for various cardiac conditions. This study aimed to compare the perioperative outcomes and follow-up results of the robotic approach versus the sternotomy approach for left atrial myxoma (LAM) resection. METHOD: We retrospectively analyzed the perioperative outcomes and follow-up results of 94 patients who underwent left atrial myxoma resection using either the sternotomy approach (n = 64) or the robotic approach (n = 30) at our center between January 2017 and April 2023. Multiple linear regressions were employed to examine the actual impact of the surgical approach on perioperative outcomes while controlling for potential confounding factors. RESULTS: There were no in-hospital deaths or follow-up deaths in the robotic group. Univariate analyses revealed that robotic LAM resection had a longer cardiopulmonary bypass (CPB) time (99.93 ± 22.30 vs. 76.28 ± 24.92, P < 0.001), longer aortic clamping time (57.80 ± 20.27 vs. 47.89 ± 18.10, P = 0.019), reduced postoperative drainage (P < 0.001), shorter mechanical ventilation time (P = 0.005), shorter postoperative bed-stay time (P < 0.001), shorter postoperative hospitalization time (P = 0.040), and higher hospital costs (P = 0.001) compared to the sternotomy group. After adjusting for baseline characteristics in a multiple regression model, a longer CPB time (B = 28.328; CI, 18.609-38.047; P < 0.001), longer aortic clamping time (B = 11.856; CI, 4.069-19.644; P = 0.003), reduced postoperative drainage (B = -200.224; CI, -254.962- -145.486; P < 0.001), shorter mechanical ventilation time (B = -3.429; CI, -6.562- -0.295; P = 0.032), shorter postoperative bed-stay time (B = -2.230; CI, -3.267- -1.193; P < 0.001), shorter postoperative hospitalization time (B = -1.998; CI, -3.747- -0.250; P = 0.026), and higher hospital costs (B = 2096.866, P = 0.002) were found in the robotic group. Furthermore, the robotic group exhibited a faster return to exercise compared to the sternotomy group (Log-Rank χ2 = 34.527, P < 0.001). CONCLUSION: Both the robotic and sternotomy approaches are viable and safe options for LAM resection. However, despite the higher costs, longer CPB time, and longer aortic clamping time associated with robotic LAM resection, this technique was correlated with reduced postoperative drainage and faster postoperative recovery compared to the sternotomy technique.

Effects and mechanisms of bisphenols exposure on neurodegenerative diseases risk: A systemic review.

Environmental bisphenols (BPs) pose a global threat to human health because of their extensive use as additives in plastic products. BP residues are increasing in various environmental media (i.e., water, soil, and indoor dust) and biological and human samples (i.e., serum and brain). Both epidemiological and animal studies have determined an association between exposure to BPs and an increased risk of neurodegenerative diseases (e.g., Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis), including cognitive abnormalities and behavioral disturbances. Hence, understanding the biological responses to different BPs is essential for prevention, and treatment. This study provides an overview of the underlying pathogenic molecular mechanisms as a valuable basis for understanding neurodegenerative disease responses to BPs, including accumulation of misfolded proteins, reduction of tyrosine hydroxylase and dopamine, abnormal hormone signaling, neuronal death, oxidative stress, calcium homeostasis, and inflammation. These findings provide new insights into the neurotoxic potential of BPs and ultimately contribute to a comprehensive health risk evaluation.

Synthesis and Characterization of DOPO-Containing Poly(2,6-dimethyl-1,4-phenylene oxide)s by Oxidative Coupling Polymerization.

A set of polyphenylene oxides incorporating DOPO (9,10-dihydro-9-oxa-10-phosphaphenanthrene-10-oxide) functionality, denoted as DOPO-R-PPO, was synthesized by copolymerization of 2,6-dimethylphenol (2,6-DMP) with various DOPO-substituted tetramethyl bisphenol monomers. In the initial step, a Friedel-Crafts acylation reaction was employed to react 2,6-DMP with different acyl chlorides, leading to the formation of ketone derivatives substituted with 2,6-dimethylphenyl groups. Subsequently, the ketones, along with DOPO and 2,6-DMP, underwent a condensation reaction to yield a series of DOPO-substituted bisphenol derivatives. Finally, polymerizations of 2,6-dimethylphenol with these DOPO-substituted bisphenols were carried out in organic solvents using copper(I) bromide/N-butyldimethylamine catalysts (CuBr/DMBA) under a continuous flow of oxygen, yielding telechelic PPO oligomers with DOPO moieties incorporated into the polymer backbone. The chemical structures of the synthesized compounds were characterized using various analytical techniques, including Fourier transform infrared spectroscopy (FTIR), proton nuclear magnetic resonance (1H NMR), phosphorus nuclear magnetic resonance (31P NMR), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). When compared to conventional poly(2,6-dimethyl-1,4-phenylene oxide)s with a similar molecular weight range, all DOPO-PPOs exhibited higher glass transition temperatures, enhanced thermal degradability, and increased char yield formation at 800 °C without compromising solubility in organic solvents.

Associations between Catechol-O-methyltransferase (COMT) polymorphisms and cognitive impairments, psychiatric symptoms and tardive dyskinesia in schizophrenia.

INTRODUCTION: Catechol-O-methyltransferase (COMT) is a crucial enzyme involved in dopamine metabolism and has been implicated in the etiology of tardive dyskinesia (TD). We aimed to investigate the associations between COMT gene polymorphisms and the occurrence and severity of TD in a Chinese population, as well as the impact on the psychiatric symptoms and cognitive impairments observed in TD patients. METHODS: A total of 216 chronic schizophrenia patients, including 59 TD patients and 157 NTD patients, were recruited for this study. Three SNPs of the COMT gene (rs4680, rs165599 and rs4818) were selected and genotyped using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS). TD severity, psychopathology and cognitive functioning were assessed using the Abnormal Involuntary Movement Scale (AIMS), the Positive and Negative Syndrome Scale (PANSS) and the Repeated Battery for Assessment of Neuropsychological Status (RBANS), respectively. RESULTS: In TD patients, total AIMs scores were higher in carriers of the rs4680 AA genotype than in carriers of the AG and GG genotypes (p = 0.01, 0.006), carriers of the rs4818 GC and CC genotypes had higher orofacial scores than in GG genotypes (p = 0.032, 0.002). In male TD patients, carriers of the rs165599 GA genotype scored lower in the extremities and trunk scores than AA genotype carriers (p = 0.015). Moreover, in male TD patients, COMT rs4818 was associated with cognition, since the C allele carriers had significantly higher immediate memory (p = 0.043) and verbal function (p = 0.040) scores than the G allele carriers. In addition, rs165599 genotype interacted with TD diagnosis on depressed factor (p = 0.031). CONCLUSION: Within the Chinese population, COMT gene polymorphisms could potentially serve as biomarkers for the symptoms and prognosis of TD patients.

A Dual-Mechanism Targeted Bioorthogonal Prodrug Therapy.

Bioorthogonal prodrug therapies offer an intriguing two-component system that features enhanced circulating stability and controlled activation on demand. Current strategies often deliver either the prodrug or its complementary activator to the tumor with a monomechanism targeted mechanism, which cannot achieve the desired antitumor efficacy and safety profile. The orchestration of two distinct and orthogonal mechanisms should overcome the hierarchical heterogeneity of solid tumors to improve the delivery efficiency of both components simultaneously for bio-orthogonal prodrug therapies. We herein developed a dual-mechanism targeted bioorthogonal prodrug therapy by integrating two orthogonal, receptor-independent tumor-targeting strategies. We first employed the endogenous albumin transport system to generate the in situ albumin-bound, bioorthogonal-caged doxorubicin prodrug with extended plasma circulation and selective accumulation at the tumor site. We then employed enzyme-instructed self-assembly (EISA) to specifically enrich the bioorthogonal activators within tumor cells. As each targeted delivery mode induced an intrinsic pharmacokinetic profile, further optimization of the administration sequence according to their pharmacokinetics allowed the spatiotemporally controlled prodrug activation on-target and on-demand. Taken together, by orchestrating two discrete and receptor-independent targeting strategies, we developed an all-small-molecule based bioorthogonal prodrug system for dual-mechanism targeted anticancer therapies to maximize therapeutic efficacy and minimize adverse drug reactions for chemotherapeutic agents.

Genetic Susceptibility to Tardive Dyskinesia and Cognitive Impairments in Chinese Han Schizophrenia: Role of Oxidative Stress-Related and Adenosine Receptor Genes.

Objective: Tardive dyskinesia (TD) is a severe rhythmic movement disorder caused by long-term antipsychotic medication in chronic patients with schizophrenia (SCZ). We aimed to investigate the association between polymorphisms in oxidative stress-related genes (GSTM1, SOD2, NOS1, and NOS3) and adenosine receptor gene (ADORA2A), as well as their interactions, with the occurrence and severity of TD, and cognitive impairments in a Chinese Han population of SCZ patients. Methods: Two hundred and sixteen SCZ patients were recruited and divided into TD group (n=157) and non-TD group (n=59). DNA extraction was performed by a high-salt method, followed by SNP genotyping using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS). The severity of TD, psychopathology and cognitive functioning were assessed using the Abnormal Involuntary Movement Scale (AIMS), the Positive and Negative Syndrome Scale (PANSS) and the Repeated Battery for Assessment of Neuropsychological Status (RBANS), respectively. Results: The combination of GSTM1-rs738491, NOS1-rs738409 and ADORA2A-rs229883 was identified as the best three-point model to predict TD occurrence (p=0.01). Additionally, GSTM-rs738491 CC or NOS3-rs1800779 AG genotypes may be protective factors for psychiatric symptoms in TD patients. TD patients carrying the NOS1-rs738409 AG or ADORA2A-rs229883 TT genotypes exhibited poorer cognitive performance. Conclusion: Our findings suggest that the interaction of oxidative stress-related genes and adenosine receptor gene may play a role in the susceptibility and severity of TD in Chinese Han SCZ patient. Furthermore, these genes may also affect the psychiatric symptoms and cognitive function of TD patients.

Associations between polymorphisms in the cannabinoid receptor 1 gene, cognitive impairments and tardive dyskinesia in a Chinese population with schizophrenia.

OBJECTIVE: Tardive dyskinesia (TD) is a medically induced movement disorder that occurs as a result of long-term use of antipsychotic medications, commonly seen in patients with schizophrenia (SCZ). The study aimed to investigate the relationship between single nucleotide polymorphisms (SNPs) of the CNR1 gene, TD and cognitive impairments in a Chinese population with SCZ. METHODS: A total of 216 SCZ patients were recruited. The participants were divided into TD and without TD (WTD) groups using the Schooler-Kane International Diagnostic Criteria. The severity of TD was assessed using the Abnormal Involuntary Movement Scale (AIMS). Cognitive function was assessed using the Repeatable Battery for Assessment of Neuropsychological Status (RBANS) scale. Hardy-Weinberg equilibrium tests, chained disequilibrium analyses and haplotype analyses were performed using SHE-sis software. To explore the main effects of TD diagnosis, genotype and cognitive function, as well as interaction effects, analysis of covariance (ANCOVA) was employed. RESULTS: The prevalence of TD was approximately 27.3%. Significant differences were observed in the rs806368 CT genotype and rs806370 TC genotype within the hypercongenic pattern between the male TD and WTD groups (OR = 2.508, 95% CI: 1.055-5.961, p = 0.037; OR = 2.552, 95% CI: 1.073-6.069, p = 0.034). Among TD patients, those carrying the rs806368 CC genotype exhibited higher limb trunk scores (p < 0.05). Moreover, there was a statistically significant difference in visuospatial/construction between the TD and WTD groups (p = 0.04), and a borderline significant difference in visuospatial/construction when considering the interaction between TD diagnosis and genotype at the rs806368 locus (p = 0.05). CONCLUSION: CNR1 rs806368 and rs806370 polymorphisms may play a role in TD susceptibility. Additionally, CNR1 gene polymorphisms were associated with the severity of involuntary movements and cognitive impairments in TD patients.

Clinical Characteristics and Surgical Outcomes of Right Heart Myxoma and Its Comparison with Left Heart Myxoma: A Single-Center Retrospective Study.

BACKGROUND: Cardiac myxomas are commonly located in the left atrium but rarely affect the right side of the heart. We retrospectively analyzed 28 patients receiving surgical treatment for right heart myxomas at our center and aimed to summarize the clinical features and surgical outcomes of right heart myxomas. METHODS: Between May 2001 and June 2022, 244 patients with sporadic cardiac myxomas underwent complete surgical resection. Twenty-eight patients (28/244, 11.48%) were right heart myxomas. Among the 28 right heart myxoma cases, 25 underwent median sternotomy and 3 underwent robotic or total thoracoscopic procedures. The clinical features, operative information, and follow-up data of right heart myxoma were comprehensively reviewed, and clinical characteristics between right heart myxoma and left heart myxoma were also compared. RESULTS: A significant difference was noted in sex between right heart myxoma and left heart myxoma (P <.05). Right heart myxoma had a higher asymptomatic rate (17.86% vs. 3.70%, P =.007) and a lower embolization rate (3.57% vs. 30.09%, P =.003) than left heart myxoma. The most common attachment site of right heart myxoma is the atrial septum. The mean operative duration and cardiopulmonary bypass time of right heart myxoma resection were 207.71 ± 53.40 minutes and 63.86 ± 29.73 minutes, respectively, with an in-hospital mortality rate of 3.57%. During the follow-up, 2 patients died of noncardiac causes. The overall 1-, 2-, and 5-year actuarial survival rates after right heart myxoma resection were 95.8%, 90.8%, and 84.7%, respectively. CONCLUSIONS: As a rare cardiac tumor, the clinical characteristics of right heart myxoma are different from typical left heart myxoma in some aspects, such as sex, asymptomatic rate, and embolization rate. Prompt surgical resection of right heart myxoma gives excellent early and midterm results.

Histamine H1 receptor antagonist attenuates catecholamine surge and organ injury after severe burns.

Severe burns induce a catecholamine surge, causing severe damage to the organism and raising the possibility of multisystem organ failure. Few strategies are generally acceptable to reduce catecholamine surge and organ injury post-burn. We have previously shown that histamine can amplify the catecholamine surge. In addition, promethazine, a first-generation histamine H1 receptor antagonist, alleviates catecholamine surge and organ injury after severe burns in rats. However, evidence is lacking on whether promethazine benefits patients after severe burns. Currently, sedation and analgesia (such as midazolam and fentanyl) are commonly required for patients after severe burns. It remains unclear if patients after severe burns derive clinical benefit from histamine H1 receptor antagonists combined with sedation and analgesia. This study investigates the therapeutic effect of promethazine on patients after severe burns. Moreover, we test the therapeutic effect of cetirizine, a second-generation histamine H1 receptor antagonist, combined with sedation and analgesia in rats after severe burns. We find that promethazine-pethidine treatment shows a tendency for a lower level of total bilirubin than midazolam-fentanyl in patients 7-day after severe burn. Our study confirms that cetirizine combined with midazolam and fentanyl reduces catecholamine surge and liver and lung damage after severe burns in rats; the effects are better than midazolam and fentanyl treatment. In summary, for the first time, we suggest that histamine H1 receptor antagonist has the potential clinical value of reducing liver injury in patients after severe burns. In addition, we reveal that cetirizine combined with midazolam and fentanyl may be an ideal strategy for treating severe burns.

A comparison of total thoracoscopic versus robotic approach for cardiac myxoma resection: a single-center retrospective study.

Advances in instrumentation and technique have facilitated minimally invasive surgeries for cardiac myxoma treatment. This study aims to compare the clinical outcomes between the thoracoscopic and robotic approaches for myxoma resection. Intraoperative data and postoperative data of 46 patients who underwent either thoracoscopic (n = 15) or robotic (n = 31) cardiac myxoma resection in our center between July 2013 and September 2022 were retrospectively compared. There was no in-hospital death in either group. Meanwhile, the operative time and cardiopulmonary bypass time were significantly shorter in the robotic group than in thoracoscopic group (P = 0.015 and P = 0.035, respectively). Furthermore, shorter ICU stays (P = 0.006), shorter postoperative mechanical ventilation time (P = 0.035) and less thoracic drainage (P = 0.040) were observed in the robotic group. However, the operating room costs and total hospital costs were both significantly lower in thoracoscopic group (P = 0.004 and P = 0.007, respectively). There was no significant difference between two groups regarding the incidence of postoperative complications (P > 0.05). Lastly, a faster return to exercise was noted in robotic group than in thoracoscopic group (Log-Rank χ2 = 4.094, P = 0.043). Both approaches can be safe and feasible for myxoma resection. However, regardless of higher expenses, the robotic myxoma resection approach provides shorter operation time, less postoperative thoracic drainage, and faster recovery than total thoracoscopic technique.

Discovery and characterization of a novel cGAS covalent inhibitor for the treatment of inflammatory bowel disease.

Cyclic GMP-AMP synthase (cGAS), a cytosolic DNA sensor, acts as a nucleotidyl transferase that catalyzes ATP and GTP to form cyclic GMP-AMP (cGAMP) and plays a critical role in innate immunity. Hyperactivation of cGAS-STING signaling contributes to hyperinflammatory responses. Therefore, cGAS is considered a promising target for the treatment of inflammatory diseases. Herein, we report the discovery and identification of several novel types of cGAS inhibitors by pyrophosphatase (PPiase)-coupled activity assays. Among these inhibitors, 1-(1-phenyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazin-2-yl)prop-2-yn-1-one (compound 3) displayed the highest potency and selectivity at the cellular level. Compound 3 exhibited better inhibitory activity and pathway selectivity than RU.521, which is a selective cGAS inhibitor with anti-inflammatory effects in vitro and in vivo. Thermostability analysis, nuclear magnetic resonance and isothermal titration calorimetry assays confirmed that compound 3 directly binds to the cGAS protein. Mass spectrometry and mutation analysis revealed that compound 3 covalently binds to Cys419 of cGAS. Notably, compound 3 demonstrated promising therapeutic efficacy in a dextran sulfate sodium (DSS)-induced mouse colitis model. These results collectively suggest that compound 3 will be useful for understanding the biological function of cGAS and has the potential to be further developed for inflammatory disease therapies.

Discovery and identification of a novel small molecule BCL-2 inhibitor that binds to the BH4 domain.

The B-cell lymphoma 2 (BCL-2) protein family plays a pivotal role in regulating the apoptosis process. BCL-2, as an antiapoptotic protein in this family, mediates apoptosis resistance and is an ideal target for cell death strategies in cancer therapy. Traditional treatment modalities target BCL-2 by occupying the hydrophobic pocket formed by BCL-2 homology (BH) domains 1-3, while in recent years, the BH4 domain of BCL-2 has also been considered an attractive novel target. Herein, we describe the discovery and identification of DC-B01, a novel BCL-2 inhibitor targeting the BH4 domain, through virtual screening combined with biophysical and biochemical methods. Our results from surface plasmon resonance and cellular thermal shift assay confirmed that the BH4 domain is responsible for the interaction between BCL-2 and DC-B01. As evidenced by further cell-based experiments, DC-B01 induced cell killing in a BCL-2-dependent manner and triggered apoptosis via the mitochondria-mediated pathway. DC-B01 disrupted the BCL-2/c-Myc interaction and consequently suppressed the transcriptional activity of c-Myc. Moreover, DC-B01 inhibited tumor growth in vivo in a BCL­2­dependent manner. Collectively, these results indicate that DC-B01 is a promising BCL-2 BH4 domain inhibitor with the potential for further development.

Maize plant detection using UAV-based RGB imaging and YOLOv5.

In recent years, computer vision (CV) has made enormous progress and is providing great possibilities in analyzing images for object detection, especially with the application of machine learning (ML). Unmanned Aerial Vehicle (UAV) based high-resolution images allow to apply CV and ML methods for the detection of plants or their organs of interest. Thus, this study presents a practical workflow based on the You Only Look Once version 5 (YOLOv5) and UAV images to detect maize plants for counting their numbers in contrasting development stages, including the application of a semi-auto-labeling method based on the Segment Anything Model (SAM) to reduce the burden of labeling. Results showed that the trained model achieved a mean average precision (mAP@0.5) of 0.828 and 0.863 for the 3-leaf stage and 7-leaf stage, respectively. YOLOv5 achieved the best performance under the conditions of overgrown weeds, leaf occlusion, and blurry images, suggesting that YOLOv5 plays a practical role in obtaining excellent performance under realistic field conditions. Furthermore, introducing image-rotation augmentation and low noise weight enhanced model accuracy, with an increase of 0.024 and 0.016 mAP@0.5, respectively, compared to the original model of the 3-leaf stage. This work provides a practical reference for applying lightweight ML and deep learning methods to UAV images for automated object detection and characterization of plant growth under realistic environments.

Photobiomodulation promotes angiogenesis in wound healing through stimulating the nuclear translocation of VEGFR2 and STAT3.

In recent years, Photobiomodulation (PBM) has gained prevalence as a kind of physical therapy for wound healing, however, concerning specific cellular mechanisms induced by PBM remains uncertain. The objective of this study is to evaluate the mechanisms of action of PBM (632.8 nm) on angiogenesis in wound healing in vitro and vivo. In the present work, we indicated that PBM with 1.0 J/cm2 irradiation dose exerts positive effects on cell viability, migration, proliferation and tube formation in human umbilical vein endothelial cells (HUVECs). Furthermore, we demonstrate that the VEGFA/VEGFR2/STAT3 pathway plays an important role in PBM effecting cellular function and promoting angiogenesis in wound healing. In addition, we also found that PBM activated the VEGFA/VEGFR2/STAT3 pathway by stimulating VEGFR2 and STAT3 nuclear translocation in the presence of importin-ß. Our research offer a new insight into the potential molecular mechanisms in which PBM promotes angiogenesis in wound healing.

Lactylation of PKM2 Suppresses Inflammatory Metabolic Adaptation in Pro-inflammatory Macrophages.

Emerging evidence suggests that metabolic adaptation is a vital hallmark and prerequisite for macrophage phenotype transition. Pyruvate kinase M2 (PKM2) is an essential molecular determinant of metabolic adaptions in pro-inflammatory macrophages. Post-translational modifications play a central role in the regulation of PKM2. However, doubt remains on whether lactylation in PKM2 exists and how lactylation modulates the function of PKM2. For the first time, our study reports that lactate inhibits the Warburg effect by activating PKM2, promoting the transition of pro-inflammatory macrophages towards a reparative phenotype. We identify PKM2 as a lactylation substrate and confirm that lactylation occurs mainly at the K62 site. We find that lactate increases the lactylation level of PKM2, which inhibits its tetramer-to-dimer transition, promoting its pyruvate kinase activity and reducing nuclear distribution. In short, our study reports a novel post-translational modification type in PKM2 and clarifies its potential role in regulating inflammatory metabolic adaptation in pro-inflammatory macrophages.

LYTIC COCKTAIL ATTENUATES CATECHOLAMINE SURGE AFTER SEVERE BURNS BY BLOCKING HISTAMINE H1 RECEPTOR/PKA/CREB/TYROSINE HYDROXYLASE SIGNALING IN CHROMAFFIN CELLS.

ABSTRACT: Severe burns develop a catecholamine surge, inducing severe damage to the organism, raising the possibility of multisystem organ failure, and even death. The mechanisms of catecholamine surge have not been fully elucidated, and few strategies are generally acceptable to reduce catecholamine surge postburn. Thus, it is valuable to investigate the underlying mechanisms of catecholamine surge postburn to develop targeted interventions to attenuate it. We have found that the lytic cocktail alleviates the surge of catecholamine and organ injury after severe burn; however, the underlying mechanisms were still unclear. Moreover, the lytic cocktail has side effects, such as significant arterial hypotension and breathing depression, limiting its clinical application. This study aims to investigate the therapeutic mechanism of the lytic cocktail in regulating catecholamine levels postburn. We find that promethazine, a classic histamine H1 receptor blocker and a component of the lytic cocktail, can effectively reduce catecholamine surge and organ injury postburn. Our study confirms that blood histamine levels increase after severe burns. We find that histamine can amplify the catecholamine surge by elevating tyrosine hydroxylase expression and catecholamine synthesis in chromaffin cells through the histamine H1 receptor/Protein Kinase A /cAMP-response element binding protein signaling pathway. In summary, for the first time, we find that histamine plays a vital role in catecholamine surge postburn. We also confirm that the lytic cocktail effectively alleviates catecholamine surge and organ injury postburn through promethazine.

Optimization of Spray-Drying Process Parameters to Study Anti-Sticking Effect of Hydroxypropyl Methyl Cellulose-VLV on Corni fructus Extracts.

To prevent the sticking of Corni fructus extract (CFE) during spray drying, the anti-sticking effects of different excipients were compared. Hydroxypropyl methylcellulose (HPMC)-VLV showed a higher powder yield at a lower dosage (8% of total solids), and a lower solution viscosity, compared with HPMC-E5. Therefore, HPMC-VLV is a more effective excipient for reducing CFE sticking during spray drying. The spray-drying process parameters were optimized by central composite rotatable design/response surface methodology, and spray drying was conducted under the following conditions: Inlet air temperature, 126 °C; atomization pressure, 1.05 bar; pump speed, 7.7 mL/min. Scanning electron microscopy showed that the powder comprised shrunken spherical particles with particle sizes in the range of 2-30 µm. Analysis of dynamic surface tension and chemical elements on the powder surface showed that HPMC-VLV rapidly moved to the droplet surface owing to its surface activity. HPMC covered the droplet surface and reduced surface tension, achieving an anti-sticking effect. In conclusion, HPMC-VLV at a solid content of 8% significantly improved the spray drying and reduced sticking of CFE. The spray-drying process parameters were nonlinearly related to the dry product yield. Graphical Abstract.

Super-Enhancer Induced IL-20RA Promotes Proliferation/Metastasis and Immune Evasion in Colorectal Cancer.

Unveiling key oncogenic events in malignancies is the key to improving the prognosis and therapeutic outcome of malignancies. Lines of evidence have shown that super-enhancers control the expression of genes that determine the cell fate, but the oncogenic super-enhancers in colorectal cancer (CRC) and their impact on carcinogens remain largely unexplored. Here, we identified a new oncogenic super-enhancer-regulated gene, IL-20RA, in CRC. Using the integrative analysis of H3K27ac ChIP-seq and RNA-seq in CRC tumors and normal colon tissues, we obtained a series of oncogenic super-enhancers in CRC. We found that super-enhancer inhibition by JQ-1 or iBET-151 suppressed the growth of tumor cells and inhibited the expression of IL-20RA. We found that IL-20RA was highly expressed in the tumor tissue of CRC and related to the advanced stage. Further functional studies showed that knockdown of IL-20RA inhibited the growth and metastasis of CRC. In addition, we found that IL-20RA was involved in regulating oncogenic and immune pathways and affecting the expression of genes related to cell proliferation and immune evasion in CRC. Together, our study demonstrated a novel oncogene in CRC and shed new light on oncogenic super-enhancer contributions to cell proliferation and immune escape.

RUNX1 regulates TGF-ß induced migration and EMT in colorectal cancer.

Colorectal cancer (CRC) was one of the most malignant tumors worldwide due to its metastasis. Epithelial-to-mesenchymal transition (EMT) plays an important role in CRC migration, and transforming growth factor-ß (TGF-ß) works as a dominating cytokine in CRC EMT process. Here, we originally identified RUNX1 as an important factor among TGF-ß induced EMT in CRC. We found that RUNX1 was overexpressed with the treatment of TGF-ß, accompanied with enhanced cancer cell migration and EMT which was characterized by up-graded N-Cadherin levels. Vice versa, knockdown of RUNX1 attenuated the migration ability of TGF-ß induced CRC cells. In addition, decreased expression of N-Cadherin suggested that EMT was also attenuated after knocking down RUNX1. Similar decrease was observed in EMT regulator snail family transcriptional repressor 1 (SNAI1). And the knockdown effect of RUNX1 cannot be reversed by the addition of TGF-ß. Moreover, we observed that RUNX1 expression was higher in CRC tumor tissues than in normal epithelial tissues. The enhanced expression was detected in cancer cell nucleus. These results revealed RUNX1 could regulate colorectal cancer migration via TGF-ß signaling pathway, and RUNX1 might serve as a potential target for preventing CRC metastasis.