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BACKGROUND AND OBJECTIVES: Envafolimab is the first and only globally approved subcutaneously injectable PD-L1 antibody for the treatment of instability-high (MSI-H) or DNA mismatch repair deficient (dMMR) advanced solid tumors in adults, including those with advanced colorectal cancer that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. The aim of this investigation was to examine the pharmacokinetic and exposure-response (E-R) profile of envafolimab in patients with solid tumors to support the approval of fixed and alternative dose regimens. METHODS: In this study, a population pharmacokinetic (PopPK) modeling approach will be employed to quantitatively evaluate intrinsic and extrinsic covariates. Additionally, PopPK-estimated exposure parameters were used to evaluate E-R relationship for safety and efficacy to provide a theoretical basis for recommending optimal treatment regimens. Simulations were performed on the dosing regimens of body weight-based regimen of 2.50 mg/kg QW, fixed dose 150 mg QW, and 300 mg Q2W for the selection of alternative dosing regimens. Data from 4 clinical studies (NCT02827968, NCT03101488, NCT03248843, and NCT03667170) were utilized. RESULTS: The PopPK dataset comprised 182 patients with 1810 evaluable envafolimab concentration records. Finally, a one-compartment model incorporating first-order absorption, first-order linear elimination, and time-dependent elimination according to an Emax function was found to accurately describe the concentration-time data of envafolimab in patients with advanced solid tumors. Creatinine clearance and country were identified as statistically significant factors affecting clearance, but had limited clinical significance. A relative flat exposure-response relationship was observed between early measures of safety and efficacy to verify that no dose adjustment is required. Simulation results indicated that 2.50 mg/kg QW, 150 mg QW, and 300 mg Q2W regimen yield similar steady-state exposure. CONCLUSIONS: No statistically significant difference was observed between weight-based and fixed dose regimens. Model-based simulation supports the adoption of a 150 mg weekly or 300 mg biweekly dosing regimen of envafolimab in the solid tumor population, as these schedules effectively balance survival benefits and safety risks.

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Locally recurrent nasopharyngeal carcinoma (NPC) presents substantial challenges in clinical management. Although postoperative re-irradiation (re-RT) has been acknowledged as a potential treatment option, standardized guidelines and consensus regarding the use of re-RT in this context are lacking. This article provides a comprehensive review and summary of international recommendations on postoperative management for potentially resectable locally recurrent NPC, with a special focus on postoperative re-RT. A thorough search was conducted to identify relevant studies on postoperative re-RT for locally recurrent NPC. Controversial issues, including resectability criteria, margin assessment, indications for postoperative re-RT, and the optimal dose and method of re-RT, were addressed through a Delphi consensus process. The consensus recommendations emphasize the need for a clearer and broader definition of resectability, highlighting the importance of achieving clear surgical margins, preferably through an en bloc approach with frozen section margin assessment. Furthermore, these guidelines suggest considering re-RT for patients with positive or close margins. Optimal postoperative re-RT doses typically range around 60 Gy, and hyperfractionation has shown promise in reducing toxicity. These guidelines aim to assist clinicians in making evidence-based decisions and improving patient outcomes in the management of potentially resectable locally recurrent NPC. By addressing key areas of controversy and providing recommendations on resectability, margin assessment, and re-RT parameters, these guidelines serve as a valuable resource for clinical experts involved in the treatment of locally recurrent NPC.

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Objective:To investigate the clinical characteristics and prognosis of patients with left ventricular assist device (LVAD) implantation during the perioperative period.Methods:This retrospective study included 14 patients with end-stage heart failure who underwent LVAD implantation in the department of intensive care medicine of Nanjing Hospital Affiliated to Nanjing Medical University from February 2022 to March 2023, including 12 males and 2 females patients, the mean age was (57.6±9.8)years old. All patients were implanted with Corheart 6 implantable left ventricular assist system, did not use other mechanical assisted circulatory devices. The clinical data of enrolled patients were collected, and the clinical characteristics and prognosis during ICU treatment were analyzed.Results:Dilated cardiomyopathy (DCM) was the most common primary cause of heart failure. The results of transthoracic echocardiography showed that the left ventricular ejection fraction (0.297±0.074 vs. 0.238±0.064, P=0.031) of patients was significantly increased, while the left ventricular end diastolic diameter[69.0(65.8, 74.3)mm vs. 76.5(72.8, 83.0)mm, P=0.003]and systolic end systolic diameter[61.5(53.7, 65.3)mm vs. 68.3(63.8, 71.9)mm, P=0.005]were significantly decreased post LVAD implantation as compared to before LVAD implantation. Within one week after implantation, there was no significant difference in LVAD rotational speed, flow rate, and pulsation index ( P>0.05). During ICU treatment, dobutamine (13 cases) was the most commonly used vasoactive agent. 9 patients used phosphodiesterase Ⅲ inhibitors for perioperative pulmonary hypertension. Targeted management of volume and pressure indicators was conducted for enrolled patients to prevent postoperative right heart failure and to reduce right heart burden. Within 72 hours after LVAD implantation, the average pulmonary artery pressure of patients was 24 (22, 26) mmHg to 26 (21, 28)mmHg (1 mmHg=0.133 kPa), while the fluid balance was(-581±778)ml to(-1 209±1 134)ml. All enrolled patients survived to 28 days after LVAD implantation. The length of stay in the ICU was (8.0±1.8) days and the total length of hospital stay was 33 (29, 41)days, while the time of mechanical ventilation was 8 (5, 28)h. Conclusion:LVAD implantation can help improve left ventricular systolic function, prolong survival time so as to serve as an important means of terminal treatment or bridging therapy for heart transplantation of patients with end-stage heart failure. To strengthen the perioperative hemodynamic regulation and maintain the cardiac function of patients with LVAD implantation is the important purposes of ICU postoperative management.

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Anesthesia management of Totally thoracoscopic cardiac surgery (TTCS) has been the subject of much debate and discussion. In this single center retrospective study, we summarize the experience of clinical anesthesia management for TTCS by review the medical records of our medical center and look forward to its future development. In this retrospective study, 103 patients (49 male and 54 female) were enrolled, the mean age was 56.7 ± 14.4 years old. The participants underwent Mitral Valve Replacement (MVR) + Tricuspid Valve Annuloplasty (TVA) (42, 40.8%), Mitral Valve Annuloplasty (MVA) + TVA (38, 36.9%), MVA (21, 20.4%), and MVR (2, 1.9%)，respectively. Intraoperative hypoxemia, radiographic pulmonary infiltrates, and pneumonia were observed in 19 (18.4%), 84 (81.6%), and 13 (12.6%) patients, respectively. The LOS of ICU and POD were as follows: MVR + TVA (55.1 ± 25h, 9.9 ± 3.5 d), MVA + TVA (56.5 ± 28.4h, 9.4 ± 4.2d), MVA (37.9 ± 21.9h, 8.1 ± 2.3d) and MVR (48 ± 4.2h, 7.5 ± 2.1d). No reintubation, reoperations, postoperative cognitive dysfunction, 30-day mortality were observed in the present study. The present study demonstrated that applying this anesthesia management for TTCS associated with acceptable morbidity, intensive care unit and postoperative hospital lengths of stay. The finding from the present study might provide some new approach for Anesthesia management of TTCS.

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OBJECTIVE: In laryngeal microsurgery, the insertion of the suspension laryngoscope is a strong stimulus that may cause hemodynamic fluctuations and adverse cardiovascular events. The purpose of this study was to compare the effect of preemptive treatment with esketamine and sufentanil on maintaining hemodynamics and reducing the occurrence of adverse cardiovascular events during the insertion of suspension laryngoscope. METHODS: In this double-blind randomized controlled trial, patients undergoing general anesthesia for laryngeal microsurgery were randomly assigned (1:1) to esketamine 0.5 mg kg-1 (esketamine group) and sufentanyl 0.125 µg kg-1 (sufentanil group) before inserting the laryngoscope, respectively. RESULTS: During the insertion of suspension laryngoscope, the incidence of bradycardia (HR < 60 beats/min) was 39.3% (22/56) in esketamine group, lower than 60.0% (33/55) in sufentanil group (odds ratio [OR], 2.32 [95% CI, 1.11-5.08]; p = 0.029). The incidence of hypotension (MAP <65 mmHg) was 33.9% (19/56) in esketamine group, lower than 56.4% (31/55) in sufentanil group (odds ratio [OR], 2.52 [95% CI, 1.91-5.27]; p = 0.018). The frequency of hypotension in esketamine group was lower than that in sufentanil group (0.36 ± 0.52 vs. 0.56 ± 0.50, p = 0.035). The time-weighted average of HR dropping above 30% of baseline was smaller in esketamine group than in sufentanil group (0.52 ± 2.06 vs. 1.08 ± 2.77, p = 0.006). CONCLUSIONS: These findings showed that compared with preemptive treatment of sufentanil (0.125 µg kg-1 ), esketamine (0.5 mg kg-1 ) was effective in reducing the incidence of cardiovascular adverse events, including bradycardia and hypotension induced by the insertion of suspension laryngoscope during the laryngeal microsurgery. LEVEL OF EVIDENCE: 2 Laryngoscope, 133:3021-3027, 2023.

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The aim of this study was to understand the potential of endogenous gluten inhibiting the digestibility in vitro of wheat starch (WS) in starch-fatty acid-protein system. Therefore, the influences of gluten and whey protein isolate (WPI) on the properties, multi-scale structure and in vitro digestibility of WS in WS-oleic acid (OA)-protein system were compared. The results of digestibility in vitro indicated that the ternary system of starch-fatty acid-protein showed higher resistant starch (RS) content as well as lower rapidly digestible starch (RDS) content than the binary system of WS-OA, demonstrating protein decreased WS digestion of WS-OA system. The results of pasting properties showed that gluten and WPI both increased the viscosities of WS-OA system during the cooling period due to the formation of WS-OA-protein ternary complex. The results of swelling power and solubility analysis showed that gluten and WPI both decreased the swelling power and solubility of WS-OA binary system. Laser Confocal Raman and X-ray diffraction (XRD) studies indicated that gluten and WPI both increased the ordered degree of WS-OA binary system by decreasing the full width at half maximum (FWHM) of the peak at 480 cm-1 and increasing crystallinity degree. Strikingly, compared with WPI, gluten had greater effects on the digestibility in vitro, pasting properties and ordered degree of WS in WS-OA-protein system. Therefore, gluten as an endogenous protein has the potential application in reduction the enzymatic digestibility of WS by regulating the reassembly of starch and fatty acid during thermal processing.

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ObjectiveTransforming growth factor-β1 （TGF-β1） was used to stimulate human fetal lung fibroblast 1 （HFL1） for simulating the pathological process of idiopathic pulmonary fibrosis （IPF） and thereby the effects and mechanism of medicated serum of Bupleuri Radix against IPF were investigated. MethodTGF-β1 （10 μg·L-1） was employed to stimulate HFL1， and cells were treated with medicated serum of Bupleuri Radix （5%， 10%， 15%， 20%） for 24 h. Then cell proliferation rate was determined with cell counting kit-8 （CCK-8）. Subsequently， cells were classified into the control group （20% blank serum）， TGF-β1 group （20% blank serum and 10 μg·L-1 TGF-β1）， TGF-β1 + medicated serum of Bupleuri Radix group （5% blank serum， 15% medicated serum， and 10 μg·L-1 TGF-β1）， and TGF-β1 + SIS3 group （3 μmol·L-1 SIS3， 20% blank serum， 10 μg·L-1 TGF-β1）. Based on in situ end labeling （TUNEL） staining， the apoptosis rate was examined， and mRNA expression of apoptosis-related proteins B-cell lymphoma 2 （Bcl-2）， Bcl-2 associated X protein （Bax） and myofibroblast marker α-smooth muscle actin （α-SMA） was detected by Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR）. The protein expression of α-SMA， Ras homolog enriched in brain （Rheb）， and phosphorylated （p）-Smad3 was determined by immunofluorescence. Expression of Rheb， p-Smad3， and Smad3 was examined by Western blot. ResultThe cell proliferation rate of TGF-β1 group increased compared with that of the control group （P<0.05）. The cell proliferation rate of TGF+15% medicated serum of Bupleuri Radix group and TGF+20% medicated serum of Bupleuri Radix group decreased compared with that of the TGF-β1 group （P<0.01）. Compared with the control group， TGF-β1 group showed decrease in apoptosis rate， increase in mRNA expression of Bcl-2 and α-SMA， reduction in Bax mRNA expression， and rise of α-SMA and Rheb protein expression and p-Smad3 level （P<0.05）. Compared with TGF-β1 group， TGF-β1 + medicated serum of Bupleuri Radix group and TGF-β1 + SIS3 group demonstrated high apoptosis rate， low Bcl-2 and α-SMA mRNA expression， high Bax mRNA expression， and low α-SMA and Rheb protein expression and p-Smad3 level （P<0.05）. ConclusionMedicated serum of Bupleuri Radix can inhibit TGF-β1-induced HFL1 proliferation and fibroblast-myofibroblast transition and promote fibroblast apoptosis by regulating the Smad3/Rheb axis.

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Lactic acid is one of the main metabolites in the body, and its clearance rate reflects the dynamic changes of lactic acid in the body. Recent studies have shown that lactate clearance rate is related to the prognosis of critically ill patients with sepsis/septic shock, cardiogenic shock, out-of-hospital cardiac arrest, postoperative cardiovascular surgery, and liver and kidney dysfunction. This article reviews the relevant research progress of lactate metabolism and lactate clearance rate in different critically ill patients.

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Non-occlusive mesenteric ischemia(NOMI)is a series of disorders of digestive tract caused by local blood perfusion damage,which is caused by vasospasm.As an extremely dangerous disease,NOMI is also a common intestinal complication in intensive care unit,especially in patients with hemodynamic instability after cardiac surgery,and the mortality is high.Cardiac surgery aims to improve the prognosis of patients,while the complication of NOMI is easy to be ignored,which hindered the recovery of postoperative patients.Due to the rapid development and lack of specific symptoms and signs,NOMI is easily misdiagnosed as other gastrointestinal complications.Therefore,timely and effective diagnosis of NOMI is the most important factor affecting the prognosis of post cardiac surgery.This review systematically summarized the related research on NOMI after cardiac surgery,and comprehensively concluded the cause,mechanism,treatment as well as prognosis of NOMI.Then we emphasized on the latest progresses of diagnostic methods for NOMI,in order to provide directions on the accurate identification and timely intervention of NOMI in clinical work.

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Objective: To discuss the clinical and genetic features of intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures (IDDBCS). Methods: The clinical and genetic records of a patient who was diagnosed with IDDBCS caused by PHF21A gene variation at Children's Hospital Capital Institute of Pediatrics in 2021 were collected retrospectively. Using " PHF21A gene" as the keyword, relevant articles were searched at CNKI, Wanfang Data and PubMed from establishment of databases to February 2023. Clinical and genetic features of IDDBCS were summarized in the combination of this case. Results: An 8 months of age boy showed overgrowth (height, weight and head circumference were all higher than the 97th percentile of children of the same age and sex) and language and motor developmental delay after birth, and gradually showed autism-like symptoms like stereotyped behavior and poor eye contact. At 8 months of age, he began to show epileptic seizures, which were in the form of a series of spastic seizures with no reaction to adrenocorticotropic hormone but a good response to vigabatrin. Physical examination showed special craniofacial appearances including a prominent high forehead, sparse eyebrows, broad nasal bridge, and downturned mouth with a tent-shaped upper lip. The patient also manifested hypotonia. Whole exome sequencing showed a de novo heterogeneous variant, PHF21A (NM_001101802.1): c.54+1G>A, and IDDBCS was diagnosed. A total of 6 articles (all English articles) were collected, involving this case and other 14 patients of IDDBCS caused by PHF21A gene variation. Clinical manifestations were intellectual disability or developmental delay (15 patients), craniofacial anomalies (15 patients), behavioral abnormalities (12 patients), seizures (9 patients), and overgrowth (8 patients). The main pathogenic variations were frameshift variations (8 patients). Conclusions: IDDBCS should be considered when patients show nervous developmental abnormalities, craniofacial anomalies, seizures and overgrowth. PHF21A gene variation detection helps to make a definite diagnosis.

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Objective: To summarize the clinical characteristics of epileptic seizure associated with neurofibromatosis type 1 (NF1). Methods: From January 2017 to July 2023 at Children's Hospital Capital Institute of Pediatrics, medical records of patients with both NF1 and epileptic seizure were reviewed in this case series study. The clinical characteristics, treatment and prognosis were analyzed retrospectively. Results: A total of 15 patients(12 boys and 3 girls) were collected. Café-au-lait macules were observed in all 15 patients. There were 6 patients with neurodevelopmental disorders and the main manifestations were intellectual disability or developmental delay. The age at the first epileptic seizure was 2.5 (1.2, 5.5) years. There were various seizure types, including generalized tonic-clonic seizures in 8 patients, focal motor seizures in 6 patients, epileptic spasm in 4 patients, tonic seizures in 1 patient, absence in 1 patient, generalized myoclonic seizure in 1 patient and focal to bilateral tonic-clonic seizure in 1 patient. Among 14 patients whose brain magnetic resonance imaging results were available, there were abnormal signals in corpus callosum, basal ganglia, thalamus or cerebellum in 6 patients, dilated ventricles of different degrees in 3 patients, blurred gray and white matter boundary in 2 patients, agenesis of corpus callosum in 1 patient and no obvious abnormalities in the other patients. Among 13 epilepsy patients, 8 were seizure-free with 1 or 2 antiseizure medications(ASM), 1 with drug resistant epilepsy was seizure-free after left temporal lobectomy, and the other 4 patients who have received 2 to 9 ASM had persistent seizures. One patient with complex febrile convulsion achieved seizure freedom after oral administration of diazepam on demand. One patient had only 1 unprovoked epileptic seizure and did not have another seizure without taking any ASM. Conclusions: The first epileptic seizure in NF1 patients usually occurs in infancy and early childhood, with the main seizure type of generalized tonic-clonic seizure and focal motor seizure. Some patients have intellectual disability or developmental delay. Most epilepsy patients achieve seizure freedom with ASM.

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Objective To explore left ventricular longitudinal systolic function changes during perioperative period of coronary artery bypass graft(CABG).Methods Totally 41 patients with confirmed coronary artery disease(CAD)who underwent CABG were prospectively enrolled.The preoperative left ventricular global longitudinal strain(GLS),as well as GLS on the day of CABG,on the 3rd and 7th day postoperation were measured.According to preoperative left ventricular GLS,the patients were divided into 3 groups,i.e.normal group(group A,GLS≤-18.1％,n=6),mildly decreased group(group B,-18.1％＜GLS≤-14.0％,n=22)and severely decreased group(group C,GLS＞-14.0％,n=13).Repeated measures analysis of variance,generalized estimating equation and multiple comparisons were used to analyze left ventricular systolic function in different perioperative time points.Results No significant difference of GLS was found among different time points during perioperative period of CABG in group A and C(all adjusted P＞0.05).In group B,GLS on postoperative days were lower than that before CABG(all adjusted P＜0.001),and the lowest value was observed on the day of CABG postoperatively,while no significant difference of GLS was found between the 3rd and 7th day postoperation(adjusted P=1.00).Compared with those before CABG,the longitudinal strain(LS)of basal segment on the day of CABG postoperatively and 3rd day postoperation,of middle segment and apical segment at all postoperative time points were lower(all adjusted P＜0.05),while of the apical segment on the day of CABG postoperatively decreased most obviously.No significant difference of LS of each ventricular segment was found between the 3rd nor the 7th day postoperation(all adjusted P＞0.05).Conclusion GLS decreased significantly on the day of CABG postoperatively but partially recovered within the following week in CAD patients with mildly decreased preoperative GLS.CABG had the most pronounced effect on LS of apical segment in left ventricle.

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TICRR is a regulatory factor of DNA replication with ToPBP1 interaction. At present, the underlying function and mechanisms of TICRR remain unclear in LIHC. Our objective was to assess the function and prognosis of TICRR in LIHC. We conducted a differential expression analysis, GO/KEGG, and GSEA enrichment analysis of TICRR in LIHC. We also carried out the gene frequency and SCNA of TICRR. We found that TICRR could serve as an independent prognostic marker in LIHC by univariate and multivariate analysis. In addition, we observed that TICRR was related to immune infiltration, and TICRR had positive correlation with PD1/PD-L1 and CTLA-4 in LIHC. The hsa-miR-126-3p/IPO9-AS1 may be the candidate ncRNAs to regulate the expression of TICRR. The high rate of SCNV of TICRR might have critical effect on the function of CTL cells in LIHC. We further demonstrate through a series of experiments that TICRR facilitated the proliferation and metastasis of liver cancer cells in vitro. Altogether, TICRR might be a potential biomarker and therapeutic target in LIHC.

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BACKGROUND: This study aimed to examine the effect of sodium butyrate on severe acute pancreatitis-related gut barrier injury in a rat model and explore its mechanism. METHODS: Male rats randomly fell into 3 groups, that is, the control, the severe acute pancreatitis group, and the severe acute pancreatitis+butyrate group. Rats in the control group received sham operation, while rats in the severe acute pancreatitis group and severe acute pancreatitis+butyrate group received severe acute pancreatitis induction by intraductal infusion of 4% sodium taurocholate. After that, rats in the severe acute pancreatitis+butyrate group were fed with sodium butyrate solution with free access. Intestinal barrier injury was measured based on the expression of tight junction proteins by reverse transcription polymerase chain reaction, Western blotting assay as well as immunohistochemical staining. The variation of Treg cells was measured by reverse transcription polymerase chain reaction, Western blotting assay, immunohistochemical staining, and flow cytometry analysis. RESULTS: Compared to rats in the control, rats in the severe acute pancreatitis group showed significantly higher pathohistological scores (P < .001) in the intestine, as well as decreased expression of occludin and ZO-1. While, rats in the severe acute pancreatitis+butyrate group showed mitigated histologic lesions (P < .05) and increased expressions of occludin and ZO-1. In addition, rats in the severe acute pancreatitis group showed the obvious reduction in the expressions of Foxp3 and GPR109a and the decreased percentage of Treg cells in the intestine (P < .001) compared to rats in the control. However, rats in the severe acute pancreatitis+butyrate group showed markedly increased expressions of Foxp3 and GPR109a and the upregulated percentage of Treg cells (P < .01). CONCLUSION: Butyrate could significantly mitigate the intestinal injury induced by severe acute pancreatitis, probably by inducing the differentiation of Treg cells.

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Background and aims: Inflammatory bowel disease (IBD) places a heavy medical burden on countries and families due to repeated and prolonged attacks, and the incidence and prevalence of IBD are increasing worldwide. Therefore, finding an effective treatment is a matter of great urgency. Glycerol monolaurate (GML), which has a twelve-carbon chain, is a compound naturally found in human breast milk. Some studies have shown that GML has antibacterial and anti-inflammatory effects. However, the specific mechanism of action remains unclear. Methods: Acute colitis was established in mice using 3% DSS, and glycerol monolaurate (500 mg·kg-1) was administered for two weeks. QPCR and western blotting were performed to examine the inflammatory status. Mice described were subjected to flow cytometry analysis for immune cell activation. Results: GML treated alleviated macroscopic symptoms such as shortened colons, increased spleen weight, and caused weight loss in mice with DSS-induced colitis. In addition, GML decreased the expression of pro-inflammatory factors (NF-α, IL-1ß and IL-1α) and increased the expression of anti-inflammatory factors (IL-10 and TGF-ß). GML inhibited the activation of the MAPK and NF-κB signalling pathways, improved tissue damage, and increased the expression of intestinal tight junction proteins. In addition, LPMCs extracted from intestinal tissue via flow cytometry showed that GML treatment led to a decrease of Th17 cells, Neutrophils and Macrophages. 16S rDNA sequencing showed that GML increased the abundance of commensal bacterium such as Akkermansia and Lactobacillus murinus. Conclusions: We showed that oral administration of GML ameliorated DSS-induced colitis by inhibiting infiltration of Th17 cells, Neutrophils, and Macrophages, protecting the intestinal mucosal barrier and altered the abundance of commensal bacterium. This study provides new insights into the biological function and therapeutic potential of GML in the treatment of IBD.

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Nasopharyngeal carcinoma (NPC) has a 10-15% recurrence rate, while no long term or durable treatment options are currently available. Single-cell profiling in recurrent NPC (rNPC) may aid in designing effective anticancer therapies, including immunotherapies. For the first time, we profiled the transcriptomes of ∼60,000 cells from four primary NPC and two rNPC cases to provide deeper insights into the dynamic changes in rNPC within radiation fields. Heterogeneity of both immune cells (T, natural killer, B, and myeloid cells) and tumor cells was characterized. Recurrent samples showed increased infiltration of regulatory T cells in a highly immunosuppressive state and CD8+ T cells in a highly cytotoxic and dysfunctional state. Enrichment of M2-polarized macrophages and LAMP3+ dendritic cells conferred enhanced immune suppression to rNPC. Furthermore, malignant cells showed enhanced immune-related features, such as antigen presentation. Elevated regulatory T cell levels were associated with a worse prognosis, with certain receptor-ligand communication pairs identified in rNPC. Even with relatively limited samples, our study provides important clues to complement the exploitation of rNPC immune environment and will help advance targeted immunotherapy of rNPC.

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Nasopharyngeal carcinoma (NPC) is a malignant epithelial tumor originating in the nasopharynx and has a high incidence in Southeast Asia and North Africa. To develop these comprehensive guidelines for the diagnosis and management of NPC, the Chinese Society of Clinical Oncology (CSCO) arranged a multi-disciplinary team comprising of experts from all sub-specialties of NPC to write, discuss, and revise the guidelines. Based on the findings of evidence-based medicine in China and abroad, domestic experts have iteratively developed these guidelines to provide proper management of NPC. Overall, the guidelines describe the screening, clinical and pathological diagnosis, staging and risk assessment, therapies, and follow-up of NPC, which aim to improve the management of NPC.

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Hepatitis B (HB) is a globally prevalent infectious disease caused by the HB virus. Xiaochaihu decoction (XCHD) is a classic herbal formula with a long history of clinical application in treating HB. Although the anti-HB activity of XCHD has been reported, systematic research on the exact mechanism of action is lacking. Here, a network pharmacology-based approach was used to predict the active components, important targets, and potential mechanism of XCHD in HB treatment. Investigation included drug-likeness evaluation; absorption, distribution, metabolism, and elimination (ADME) screening; protein-protein interaction (PPI) network construction and cluster analysis; Gene Ontology (GO) analysis; and Kyoto Encyclopedia of Genes and Genomes (KEGG) annotation. Molecular docking was adopted to investigate the interaction between important target proteins and active components. Eighty-seven active components of XCHD and 155 anti-HB targets were selected for further analysis. The GO enrichment and similarity analysis results indicated that XCHD might perform similar or the same GO functions. Glycyrrhizae Radix (GR), one of the seven XCHD herbs, likely exerts some unique GO functions such as the regulation of interleukin-12 production, positive regulation of interleukin-1 beta secretion, and regulation of the I-kappaB/NF-kappaB complex. The PPI network and KEGG pathway analysis results showed that XCHD affects HB mainly through modulating pathways related to viral infection, immunity, cancer, signal transduction, and metabolism. Additionally, molecular docking verified that the active compounds (quercetin, chrysin, and capsaicin) could bind with the key targets. This work systematically explored the anti-HB mechanism of XCHD and provides a novel perspective for future pharmacological research.

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OBJECTIVE: We evaluated the effects and mechanisms of GDC0623 on osteogenic differentiation of osteoblasts induced by IL-1ß. Methodology. Osteoblasts were treated with 20 ng/ml IL-1ß and 0.1 µM GDC0623. Cell proliferation levels were evaluated by the cell counting kit 8 (CCK8), EdU assay, and western blotting [proliferating cell nuclear antigen (PCNA) and Cyclin D1]. Osteoblasts were cultured in an osteogenic induction medium for 1-3 weeks after which their differentiations were assessed by alkaline phosphatase (ALP) staining, Alizarin Red staining, calcium concentration, immunocytochemistry staining, real-time quantitative PCR (RT-qPCR), and immunofluorescence staining. The osteogenesis-associated mechanisms were further evaluated by western blotting using appropriate antibodies. RESULTS: Relative to the control group, IL-1ß induced the rapid proliferation of osteoblasts and suppressed their osteogenic differentiations by upregulating the activities of MEK-Erk1/2 as well as Jak-Stat3 pathways and by elevating MMP13 and MMP9 levels. However, blocking of the MEK-Erk1/2 signaling pathway by GDC0623 treatment reversed these effects. CONCLUSION: Inhibition of Jak-Stat3 pathway by C188-9 downregulated the expression levels of MMP9 and MMP13, activated MEK-Erk1/2 pathway, and inhibited osteogenic differentiation.

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This article is concerned with the problem of dissipativity and stability analysis for a class of neural networks (NNs) with time-varying delays. First, a new augmented Lyapunov-Krasovskii functional (LKF), including some delay-product-type terms, is proposed, in which the information on time-varying delay and system states is taken into full consideration. Second, by employing a generalized free-matrix-based inequality and its simplified version to estimate the derivative of the proposed LKF, some improved delay-dependent conditions are derived to ensure that the considered NNs are strictly ( Q , S , R )- γ -dissipative. Furthermore, the obtained results are applied to passivity and stability analysis of delayed NNs. Finally, two numerical examples and a real-world problem in the quadruple tank process are carried out to illustrate the effectiveness of the proposed method.