Methionine-choline deficient diet deteriorates DSS-induced murine colitis through disturbance of gut microbes and infiltration of macrophages.

Ulcerative colitis (UC) is associated with changed dietary habits and mainly linked with the gut microbiota dysbiosis, necroptosis of epithelial cells, and mucosal ulcerations. Liver dysfunction and abnormal level of liver metabolism indices were identified in UC patients, suggesting a close interaction between gut and liver disorders. Methionine-choline deficient diet (MCD) has been shown to induce persistent alterations of gut microbiota and metabolome during hepatitis. In this study we further explored the disease phenotypes in UC patients and investigated whether MCD functioned as a trigger for UC susceptibility. After assessing 88 serum specimens from UC patients, we found significant liver dysfunction and dyslipidemia including abnormal ALT, AST, TG, TC, LDL-c and HDL-c. Liver dysfunction and dyslipidemia were confirmed in DSS-induced colitis mice. We fed mice with MCD for 14 days to cause mild liver damage, and then treated with DSS for 7 days. We found that MCD intake significantly exacerbated the pathogenesis of mucosal inflammation in DSS-induced acute, progressive, and chronic colitis, referring to promotion of mucosal ulcers, colon shortening, diarrhea, inflammatory immune cell infiltration, cytokines release, and abnormal activation of inflammatory macrophages in colon and liver specimens. Intraperitoneal injection of clodronate liposomes to globally delete macrophages dramatically compromised the pathogenesis of MCD-triggering colitis. In addition, MCD intake markedly changed the production pattern of short-chain fatty acids (SCFAs) in murine stools, colons, and livers. We demonstrated that MCD-induced colitis pathogenesis largely depended on the gut microbes and the disease phenotypes could be transmissible through fecal microbiota transplantation (FMT). In conclusion, this study supports the concept that intake of MCD predisposes to experimental colitis and enhances its pathogenesis via modulating gut microbes and macrophages in mice.

RIPK1 inhibitor ameliorates pulmonary injury by modulating the function of neutrophils and vascular endothelial cells.

Acute lung injury (ALI) is an acute and progressive hypoxic respiratory failure that could progress to acute respiratory distress syndrome (ARDS) with a high mortality rate, thus immediate medical attention and supportive care are necessary. The pathophysiology of ALI is characterized by the disruption of the alveolar-capillary barrier and activation of neutrophils, leading to lung tissue damage. The receptor-interacting protein kinase 1 (RIPK1) has emerged as a promising target for the treatment of multiple inflammatory diseases, but the role of RIPK1 in the ALI remains poorly understood. In this study, we aimed to figure out the pathological role of RIPK1 in ALI, especially in the pulmonary immune microenvironment involving neutrophils and endothelial cells. In vivo experiments showed that RIPK1 inhibitor protected against lipopolysaccharide (LPS)-induced lung injury in mouse models, with reduced neutrophils and monocytes infiltration in the lungs. Further studies demonstrated that, besides the inhibitory action on necroptosis, RIPK1 inhibitor directly suppressed reactive oxygen species (ROS) generation and inflammatory cytokines secretion from neutrophils. Furthermore, RIPK1 inhibition maintains the barrier function in TNF-α-primed vascular endothelial cells and prevents their activation induced by the supernatant from LPS-stimulated neutrophils. Mechanistically, the aforementioned effects of RIPK1 inhibitor are associated with the NF-κB signaling pathway, which is partially independent of necroptosis inhibition. These results provide new evidence that RIPK1 inhibitor directly regulates the function of neutrophils and endothelial cells, as well as interferes with the interactions between these two cell types, therefore contributing to a better understanding of RIPK1 in ALI and providing a potential avenue for future therapeutic interventions.

Sodium nitroprusside improved the quality of Radix Saposhnikoviae through constructed physiological response under ecological stress.

The ecological significance of secondary metabolites is to improve the adaptive ability of plants. Secondary metabolites, usually medicinal ingredients, are triggered by unsuitable environment, thus the quality of medicinal materials under adversity being better. The quality of the cultivated was heavily declined due to its good conditions. Radix Saposhnikoviae, the dried root of Saposhnikovia divaricata (Turcz.) Schischk., is one of the most common botanicals in Asian countries, now basically comes from cultivation, resulting in the market price being only 1/10 to 1/3 of its wild counterpart, so improving the quality of cultivated Radix Saposhnikoviae is of urgency. Nitric oxide (NO) plays a crucial role in generating reactive oxygen species and modifying the secondary metabolism of plants. This study aims to enhance the quality of cultivated Radix Saposhnikoviae by supplementing exogenous NO. To achieve this, sodium nitroprusside (SNP) was utilized as an NO provider and applied to fresh roots of S. divaricata at concentrations of 0.03, 0.1, 0.5, and 1.0 mmol/L. This study measured parameters including the activities of antioxidant enzymes, secondary metabolite synthesis enzymes such as phenylalanine ammonia-lyase (PAL), 1-aminocyclopropane-1-carboxylic acid (ACC), and chalcone synthase (CHS), as well as the contents of NO, superoxide radicals (O2·-), hydrogen peroxide (H2O2), malondialdehyde (MDA), and four secondary metabolites. The quality of Radix Saposhnikoviae was evaluated with antipyretic, analgesic, anti-inflammatory effects, and inflammatory factors. As a result, the NO contents in the fresh roots were significantly increased under SNP, which led to a significant increase of O2·-, H2O2, and MDA. The activities of important antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD), were found to increase as well, with their peak levels observed on the 2nd and 3rd days. PAL, ACC, and CHS activities were also significantly enhanced, resulting in the increased secondary metabolite contents of Radix saposhnikoviae in all groups, especially the 0.5 mmol/L SNP. The four active ingredients, prim-O-glucosylcimifugin, cimifugin, 4'-O-ß-D-glucosyl-5-O-methylvisamminol, and sec-O-glucosylhamaudol, increased by 88.3%,325.0%, 55.4%, and 283.8%, respectively, on the 3rd day. The pharmaceutical effects of Radix Saposhnikoviae under 0.5 mmol/L SNP were significantly enhanced. Exogenous SNP can induce the physiological response of S. divaricata under adverse conditions and significantly improve the quality of Radix Saposhnikoviae.

Curbing vehicular urban pollution in China: Investigating the usage intentionof public electric buses.

Public electric bus (PEB) usage remains critical in reducing carbon emissions, traffic congestion, energy consumption, resource exhaustion, and environmental pollution. PEB usage revolves around consumer acceptance, and assessing the psychological factors accounting for using PEBs is essential in mitigating these challenges for a sustainable environment. The study extends the reasoned action theory (TRA) with environmental awareness, convenience, and personal norms in investigating residents' intention to use electric buses in Nanjing, China. 405 responses were gathered through an online survey and evaluated using Structural Equation Modeling (SEM). Statistical analysis showed that the structural model (66.4%) explained public electric bus use better than the original TRA model (20.7%). Attitude, subjective norms, personal norms, environmental awareness, and convenience directly influenced the intention to use PEBs. Personal norms related to attitude positively. Environmental awareness related to personal norms in PEB use. Subjective norms partially mediated the impact of personal norms on the intention to use PEBs. Convenience moderated the interaction between personal norms and intention to use PEBs. Respondents differed in income level, educational level, and employment but not gender in their inclinations to use PEBs. The current study recommends potent policy implications to enhance and ensure the maximum use of PEBs.

Effect of glycosaminoglycans with different degrees of sulfation on chondrogenesis / 华西口腔医学杂志

OBJECTIVES@#This study aims to investigate the effects and mechanisms of chondroitin sulfate (CS), dermatan sulfate (DS), and heparin (HEP) on chondrogenesis of murine chondrogenic cell line (ATDC5) cells and the maintenance of murine articular cartilage in vitro.@*METHODS@#ATDC5 and articular cartilage tissue explant were cultured in the medium containing different sulfated glycosaminoglycans. Cell proliferation, differentiation, cartilage formation, and mechanism were observed using cell proliferation assay, Alcian blue staining, real-time quantitative polymerase chain reaction (RT-qPCR), and Western blot, respectively.@*RESULTS@#Results showed that HEP and DS primarily activated the bone morphogenetic protein (BMP) signal pathway, while CS primarily activated the protein kinase B (AKT) signal pathway, further promoted ATDC5 cell proliferation and matrix production, and increased Sox9, Col2a1, and Aggrecan expression.@*CONCLUSIONS@#This study investigated the differences and mechanisms of different sulfated glycosaminoglycans in chondrogenesis and cartilage homeostasis maintenance. HEP promotes cartilage formation and maintains the normal state of cartilage tissue in vitro, while CS plays a more effective role in the regeneration of damaged cartilage tissue.

Short-course radiotherapy combined with CAPOX and PD-1 inhibitor for the total neoadjuvant therapy of locally advanced rectal cancer: the preliminary single-center findings of a prospective, multicentre, randomized phase II trial (TORCH) / 中华胃肠外科杂志

Objective: Total neoadjuvant therapy has been used to improve tumor responses and prevent distant metastases in patients with locally advanced rectal cancer (LARC). Patients with complete clinical responses (cCR) then have the option of choosing a watch and wait (W&W) strategy and organ preservation. It has recently been shown that hypofractionated radiotherapy has better synergistic effects with PD-1/PD-L1 inhibitors than does conventionally fractionated radiotherapy, increasing the sensitivity of microsatellite stable (MSS) colorectal cancer to immunotherapy. Thus, in this trial we aimed to determine whether total neoadjuvant therapy comprising short-course radiotherapy (SCRT) combined with a PD-1 inhibitor improves the degree of tumor regression in patients with LARC. Methods: TORCH is a prospective, multicenter, randomized, phase II trial (TORCH Registration No. NCT04518280). Patients with LARC (T3-4/N+M0, distance from anus ≤10 cm) are eligible and are randomly assigned to consolidation or induction arms. Those in the consolidation arm receive SCRT (25Gy/5 Fx), followed by six cycles of toripalimab plus capecitabine and oxaliplatin (ToriCAPOX). Those in the induction arm receive two cycles of ToriCAPOX, then undergo SCRT, followed by four cycles of ToriCAPOX. Patients in both groups undergo total mesorectal excision (TME) or can choose a W&W strategy if cCR has been achieved. The primary endpoint is the complete response rate (CR, pathological complete response [pCR] plus continuous cCR for more than 1 year). The secondary endpoints include rates of Grade 3-4 acute adverse effects (AEs) etc. Results: Up to 30 September 2022, 62 patients attending our center were enrolled (Consolidation arm: 34, Induction arm:28). Their median age was 53 (27-69) years. Fifty-nine of them had MSS/pMMR type cancer (95.2%), and only three MSI-H/dMMR. Additionally, 55 patients (88.7%) had Stage III disease. The following important characteristics were distributed as follows: lower location (≤5 cm from anus, 48/62, 77.4%), deeper invasion by primary lesion (cT4 7/62, 11.3%; mesorectal fascia involved 17/62, 27.4%), and high risk of distant metastasis (cN2 26/62, 41.9%; EMVI+ 11/62, 17.7%). All 62 patients completed the SCRT and at least five cycles of ToriCAPOX, 52/62 (83.9%) completing six cycles of ToriCAPOX. Finally, 29 patients achieved cCR (46.8%, 29/62), 18 of whom decided to adopt a W&W strategy. TME was performed on 32 patients. Pathological examination showed 18 had achieved pCR, four TRG 1, and 10 TRG 2-3. The three patients with MSI-H disease all achieved cCR. One of these patients was found to have pCR after surgery whereas the other two adopted a W&W strategy. Thus, the pCR and CR rates were 56.2% (18/32) and 58.1% (36/62), respectively. The TRG 0-1 rate was 68.8% (22/32). The most common non-hematologic AEs were poor appetite (49/60, 81.7%), numbness (49/60, 81.7%), nausea (47/60, 78.3%) and asthenia (43/60, 71.7%); two patients did not complete this survey. The most common hematologic AEs were thrombocytopenia (48/62, 77.4%), anemia (47/62, 75.8%), leukopenia/neutropenia (44/62, 71.0%) and high transaminase (39/62, 62.9%). The main Grade III-IV AE was thrombocytopenia (22/62, 35.5%), with three patients (3/62, 4.8%) having Grade IV thrombocytopenia. No Grade V AEs were noted. Conclusions: SCRT-based total neoadjuvant therapy combined with toripalimab can achieve a surprisingly good CR rate in patients with LARC and thus has the potential to offer new treatment options for organ preservation in patients with MSS and lower-location rectal cancer. Meanwhile, the preliminary findings of a single center show good tolerability, the main Grade III-IV AE being thrombocytopenia. The significant efficacy and long-term prognostic benefit need to be determined by further follow-up.

Molecular mechanism and treatment strategy of colorectal cancer peritoneal metastasis / 中华胃肠外科杂志

Peritoneal metastatic colorectal cancer (pmCRC) is common and has been considered as the terminal stage. The theory of "seed and soil" and "oligometastasis" are the acknowledged hypotheses of pathogenesis of pmCRC. In recent years, the molecular mechanism related to pmCRC has been deeply researched. We realize that the formation of peritoneal metastasis, from detachment of cells from primary tumor to mesothelial adhesion and invasion, depends on the interplay of multiple molecules. Various components of tumor microenvironment also work as regulators in this process. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have been widely used in clinical practice as an established treatment for pmCRC. Besides systemic chemotherapy, targeted and immunotherapeutic drugs are also increasingly used to improve prognosis. This article reviews the molecular mechanisms and treatment strategies related to pmCRC.

Blood glucose levels and the risk of HPV multiple infections in high-grade squamous intraepithelial lesions: A retrospective cross-sectional study of Chinese patients.

Besides the controversy of the association of high glycemic index and glycemic load with precancerous cervical lesions, only a few studies have examined the impact of fasting blood glucose levels on human papillomavirus (HPV) multiple infections. In the present study, we appraised the relationship between blood glucose levels and multiple HPV infections in a population of HPV-positive women with cervical high-grade squamous intraepithelial lesions (HSIL). The present study was designed as a cross-sectional correlative analysis. A total of 560 participants with a pathologically confirmed HSIL with HPV infection were included from a hospital in China during January 1, 2018, and December 31, 2019. The target variables and the outcome variables were the glucose levels at the baseline and HPV multiplicity, respectively. The odds ratio and 95% confidence intervals were calculated to estimate the risk of multiple infections via logistic regression analysis. The average age of the 560 participants was 44.63 ± 10.61 years; the nonlinear relationship was detected between the glucose levels and multiplicity of HPV, with an inflection point at 5.4. After adjusting for the full range of variables, the effect sizes and confidence intervals for the left and right sides of the inflection points were found to be 0.379 (0.196-0.732) and 5.083 (1.592-16.229), respectively. In this cross-sectional study, both high and low blood glucose levels increased the risk of multiple HPV infections, demonstrating a U-shaped relationship between the blood glucose levels and multiple HPV infections.

HIF1α/VEGF Feedback Loop Contributes to 5-Fluorouracil Resistance.

5-Fluorouracil (5-Fu) is one of the basic drugs in colorectal cancer (CRC) chemotherapy, and its efficacy is mainly limited by the acquisition of drug resistance. However, the underlying mechanisms remain unclear. In this study, hypoxia inducible factor 1α (HIF1α) was screened for high expression in 5-Fu resistant HCT115 cells, which displayed epithelial-mesenchymal transition (EMT) phenotype. Suppression of HIF1α reversed EMT phenotype, reduced glucose transporter 1 (Glut1) expression, a key molecule mediated drug resistance. Moreover, we unveiled that vascular endothelial growth factor (VEGF) was regulated by HIF1α and mediated HIF1α-maintained malignant phenotype of 5-Fu resistant cells. Further studies verified that AKT/GSK3ß signaling was activated in resistant cells and controlled HIF1α expression. Interestingly, we demonstrated that VEGF could feedback up-regulate HIF1α via AKT/GSK3ß signaling. Clinically, HIF1α and VEGF were high expressed and associated with survival and prognosis in CRC patients. In conclusion, our findings proposed that HIF1α/VEGF feedback loop contributed to 5-Fu resistance, which might be potential therapeutic targets.

Inhibition of PDE4 by apremilast attenuates skin fibrosis through directly suppressing activation of M1 and T cells.

Systemic sclerosis (SSc) is a life-threatening chronic connective tissue disease with the characteristics of skin fibrosis, vascular injury, and inflammatory infiltrations. Though inhibition of phosphodiesterase 4 (PDE4) has been turned out to be an effective strategy in suppressing inflammation through promoting the accumulation of intracellular cyclic adenosine monophosphate (cAMP), little is known about the functional modes of inhibiting PDE4 by apremilast on the process of SSc. The present research aimed to investigate the therapeutic effects and underlying mechanism of apremilast on SSc. Herein, we found that apremilast could markedly ameliorate the pathological manifestations of SSc, including skin dermal thickness, deposition of collagens, and increased expression of α-SMA. Further study demonstrated that apremilast suppressed the recruitment and activation of macrophages and T cells, along with the secretion of inflammatory cytokines, which accounted for the effects of apremilast on modulating the pro-fibrotic processes. Interestingly, apremilast could dose-dependently inhibit the activation of M1 and T cells in vitro through promoting the phosphorylation of CREB. In summary, our research suggested that inhibiting PDE4 by apremilast might provide a novel therapeutic option for clinical treatment of SSc patients.

STING inhibitor ameliorates LPS-induced ALI by preventing vascular endothelial cells-mediated immune cells chemotaxis and adhesion.

Acute lung injury (ALI) is a common and devastating clinical disorder featured by excessive inflammatory responses. Stimulator of interferon genes (STING) is an indispensable molecule for regulating inflammation and immune response in multiple diseases, but the role of STING in the ALI pathogenesis is not well elucidated. In this study, we explored the molecular mechanisms of STING in regulating lipopolysaccharide (LPS)-induced lung injury. Mice were pretreated with a STING inhibitor C-176 (15, 30 mg/kg, i.p.) before LPS inhalation to induce ALI. We showed that LPS inhalation significantly increased STING expression in the lung tissues, whereas C-176 pretreatment dose-dependently suppressed the expression of STING, decreased the production of inflammatory cytokines including TNF-α, IL-6, IL-12, and IL-1ß, and restrained the expression of chemokines and adhesion molecule vascular cell adhesion protein-1 (VCAM-1) in the lung tissues. Consistently, in vitro experiments conducted in TNF-α-stimulated HMEC-1cells (common and classic vascular endothelial cells) revealed that human STING inhibitor H-151 or STING siRNA downregulated the expression levels of adhesion molecule and chemokines in HMEC-1cells, accompanied by decreased adhesive ability and chemotaxis of immunocytes upon TNF-α stimulation. We further revealed that STING inhibitor H-151 or STING knockdown significantly decreased the phosphorylation of transcription factor STAT1, which subsequently influenced its binding to chemokine CCL2 and adhesive molecule VCAM-1 gene promoter. Collectively, STING inhibitor can alleviate LPS-induced ALI in mice by preventing vascular endothelial cells-mediated immune cell chemotaxis and adhesion, suggesting that STING may be a promising therapeutic target for the treatment of ALI.

The mechanisms and roles of melatonin in gastrointestinal cancer.

Gastrointestinal (GI) cancer is a global health problem with wide lesions and numerous cases. The increased morbidity and mortality of GI cancer is a socio-economic challenge for decades to come. Melatonin, a nature indolamine, exerts a crucial role in molecular interactions involved in multiple functional and physiological processes. Increasing evidence indicates that melatonin can modulate GI tract, decrease the occurrence of GI cancer, and enhance the sensitivity to chemoradiotherapy. However, little is known about the exact role of melatonin in anti-carcinogenesis. In this review, we discuss the action of the beneficial effects of melatonin in GI carcinogenesis. Furthermore, we compile the understanding of the role of melatonin in GI cancer, including esophageal cancer (EC), gastric cancer (GC), hepatocellular carcinoma (HCC), colorectal cancer (CRC), and pancreatic cancer (PC). In addition, the potential therapeutic application and clinical evaluation of melatonin in GI cancer are also discussed.

Application Progress of Plant Growth Regulator in Production of Chinese Medicinal Materials / 中国实验方剂学杂志

Plant growth regulator （PGR） is mostly a class of chemical synthesis substance with physiological activities similar to plant hormones，which can promote cell elongation，induce vascular differentiation or accelerate tissue aging via regulating the physiological processes such as photosynthesis，respiration，transpiration，signal transduction，substance absorption and operation. PGR has the advantages of small dosage，high efficiency，low toxicity and less residue，and it is widely used in the planting of Chinese medicinal herbs. By consulting the relevant literature published in recent years，this paper briefly summarizes the main types of PGR，e.g.auxins，gibberellins，cytokinins，abscisic acid and ethylene，etc. On the other hand，this article analyzes and sums up the specific applications of PGR in the manufacture of Chinese herbal medicine，for instance，promoting seed germination，improving seed setting rate or fruit setting rate，dwarfing plants，inhibiting reproductive growth，regulating gender differentiation，stimulating fruit falling，enhancing resistance and so on. The problems existing in the practical use of PGR are pointed out，non-differentiation of specific species，unreasonable combination，not paying attention to the operation method，arbitrarily increasing the dose，lack of residue limit standard and reducing the content of some effective components，for example.Meanwhile，some feasible suggestions are put forward.Not only the suitable types of PGR should be selected in a reasonable and standardized manner，but also the appropriate concentration，dosage and period of application should be chosen carefully； the dual effects of PGR on plant growth and active ingredients in medicinal organs should be concerned，so as to improve the yield and avoid the loss of effective components on the basis of ensuring the quality of Chinese medicinal materials； it is necessary to strengthen the registration of PGR in the production of Chinese medicinal materials and establish residue limit standards to provide a monitoring basis for ensuring the safety of Chinese medicine in the future.The scientific use of PGR can promote the increase of agricultural yield and farmers' income，and make the healthy development of Chinese herbal medicine planting industry.

Is pre-oxygenation with high-flow nasal oxygen safe? randomized control trial of 56 cases of elderly patients during induction of general anesthesia with endotracheal intubation / 南方医科大学学报

OBJECTIVE@#To evaluate the safety of preoxygenation with high-flow nasal oxygenation in elderly patients during induction of general anesthesia with endotracheal intubation.@*METHODS@#Fifty-six elderly patients without difficult airway were randomized equally into high-flow nasal oxygen group (HF group) and conventional mask oxygen group (M group). Preoxygenation was performed for 5 min before induction of general anesthesia and endotracheal intubation. Oxygenation was maintained during laryngoscopy in HF group, and ventilation lasted until laryngoscopy in M group. For all the patients, the general data, cross-sectional area (CSA) of the gastric antrum measured by ultrasonography, arterial partial pressure of oxygen (PaO2), arterial partial pressure of carbon dioxide (PaCO2) and arterial oxygen saturation (cSO2) were recorded before preoxygenation (T1), at 5 min of preoxygenation (T2) and immediately after intubation (T3). The safety time of asphyxia, intubation time, times of mask ventilation and postoperative complications were compared between the two groups.@*RESULTS@#The general data were comparable between the two groups. After 5 min of preoxygenation, PaO2 and cSO2 were significantly increased in both groups, and PaO2 was significantly higher in HF group than in M group (F=118.108 vs 9.511, P < 0.05). Both PaO2 and cSO2 decreased after intubation, but PaO2 decreased more slowly in HF group and still remained higher than that at T1; cSO2 decreased significantly in M group to a lower level than that at T1. Compared with those in M group, the patients in HF group showed a significantly longer safety time of asphyxia (t=5.305, P < 0.05) with fewer times of mask ventilation (χ2= 6.720, P < 0.05). PaCO2 increased after intubation in both groups but was comparable between the two groups (F=3.138, P > 0.05).@*CONCLUSION@#High-flow nasal oxygen is safe, simple and effective for pre-oxygenation, which, as compared with the conventional oxygen mask, improves arterial oxygen partial pressure and prolongs the safety time of asphyxia to ensure the safety of airway management during induction of general anesthesia in elderly patients with endotracheal intubation.

Development and validation of prognostic nomograms for single large and huge hepatocellular carcinoma after curative resection.

AIM: The prediction model of postoperative survival for single large and huge hepatocellular carcinoma (SLH-HCC, diameter > 5.0 cm) without portal vein tumour thrombus has not been well established. This study aimed to develop novel nomograms to predict postoperative recurrence and survival of these patients. METHODS: Data from 2469 patients with SLH-HCC who underwent curative resection from January 2005 to December 2015 in China were retrospectively collected. Specifically, nomograms of recurrence-free survival (RFS) and overall survival (OS) using data from a training cohort were developed with the Cox regression model (n = 1012). The modes were verified in an internal validation cohort (n = 338) and an external cohort comprising four tertiary institutions (n = 1119). RESULTS: The nomograms of RFS and OS based on tumour clinicopathologic features (diameter, differentiation, microvascular invasion, α-fetoprotein), operative factors (preoperative transcatheter arterial chemoembolisation therapy, scope of liver resection and intraoperative blood transfusion), underlying liver function (albumin-bilirubin grade) and systemic inflammatory or immune status (neutrophil-to-lymphocyte ratio) achieved high C-indexes of 0.85 (95% confidence interval [CI], 0.79-0.91) and 0.86 (95% CI, 0.79-0.93) in the training cohort, respectively, which were significantly higher than those of the five conventional HCC staging systems (0.62-0.73 for RFS, 0.63-0.75 for OS). The nomograms were validated in the internal cohort (0.83 for RFS, 0.84 for OS) and external cohort (0.87 for RFS, 0.88 for OS) and had well-fitted calibration curves. Our nomograms accurately stratified patients with SLH-HCC into low-, intermediate- and high-risk groups of postsurgical recurrence and mortality. CONCLUSIONS: The two nomograms achieved optimal prediction for postsurgical recurrence and OS for patients with SLH-HCC after curative resection.

The clinical significance of spondin 2 eccentric expression in peripheral blood mononuclear cells in bronchial asthma.

BACKGROUND: Bronchial asthma (BA) was a heterogeneous disease characterized by chronic airway inflammation. Spondin 2 (SPON2) was reported to be implicated in the integrin pathway, protein metabolism, and drug-induced lupus erythematosus. The purpose of this study was to evaluate the significance of SPON2 in BA diagnosis and treatment. METHODS: Peripheral blood samples were obtained from 137 BA pediatric patients (61 mild-to-moderate BA and 76 severe BA) and 59 healthy children. Subject's information, clinical indexes, pulmonary ventilation functions were recorded in the two groups. Peripheral blood mononuclear cells (PBMCs) were isolated from patients' samples. qRT-PCR and ELISA assays were employed to examine the levels of SPON2 and inflammatory cytokines, respectively. Pearson's correlation analysis confirmed the association between SPON2 and inflammatory cytokines. Receiver operating characteristic (ROC) analysis was used to evaluate the potentials of SPON2 in terms of BA detection and discriminating against the severity of BA. RESULTS: Bioinformatics analysis showed that SPON2, OLFM4, XIST, and TSIX were significantly upregulated, while KDM5D and RPS4Y1 were reduced in BA. GO analysis verified that these six genes were mainly involved in neutrophil degranulation, neutrophil activation involved in immune response, neutrophil activation, and neutrophil-mediated immunity. After isolating PBMCs, we found that SPON2 was remarkably increased in BA pediatric group compared with healthy children, and the relative levels of SPON2 were related to the severity of BA. The receiver operating characteristic (ROC) analysis revealed the high potentials of SPON2 in BA diagnosis (AUC was 0.8080) and severity distinctions (AUCs were 0.7341 and 0.8541, respectively). Also, we found that there were significant differences in fractional exhaled nitric oxide (FeNO), forced expiratory volume in 1 s (FEV1)%, FEV1/ forced vital capacity (FVC)%, immunoglobulin E (IgE), serum eosinophils, and serum neutrophils between mild-to-moderate BA group and severe BA group. Finally, SPON2 was negatively correlated with IL-12 while positively associated with IL-4, IL-13, and IL-17A. CONCLUSIONS: SPON2 was a viable biomarker for diagnosing and degree of severity in BA, providing more insight into exploring BA and treatment's pathogenesis.

Multi-institutional validation of novel models for predicting the prognosis of patients with huge hepatocellular carcinoma.

The population of patients with huge hepatocellular carcinoma (H-HCC diameter > 10.0 cm) is an odd group that is not well adjudicated in the current staging systems, whose prognosis after curative resection varies. We aimed to develop novel models to predict the long-term outcomes of patients with H-HCC without portal vein tumor thrombus after hepatectomy. There were 1076 H-HCC patients enrolled who underwent curative liver resection in five institutions in China. In total, 670 patients were recruited from our center and randomly divided into the training cohort (n = 502) and internal validation (n = 168) cohorts. Additionally, 406 patients selected from other four centers as the external validation cohort. Novel models were constructed based on independent preoperative and postoperative predictors of postsurgical recurrence (PSR) and postsurgical mortality (PSM) determined in multivariable cox regression analysis. The predictive accuracy and discriminative ability of the model were measured using Harrell's concordance index (C index) and calibration curve and compared with five conventional HCC staging systems. PSR model and PSM model were constructed based on tumor number, microscopic vascular invasion, tumor differentiation, preoperative alpha-fetoprotein level, albumin-bilirubin grade, liver segment invasion, neutrophil-to-lymphocyte ratio or platelet-to-neutrophil ratio, and surgical margin or intraoperative blood transfusion. The C-indexes were 0.84 (95% CI, 0.78-0.90) and 0.85 (95% CI, 0.78-0.91) for the PSR and PSM models, respectively, which were substantially higher than those of the five conventional HCC staging systems (0.63-0.75 for PSR; 0.66-0.77 for PSM). The two novel models achieved more accurate prognostic predictions of PSR and PSM for H-HCC patients after curative liver resection.

Peripheral blood inflammation indices are effective predictors of anastomotic leakage in elective esophageal surgery.

BACKGROUND: This study investigated the predictive value of peripheral inflammatory indices, including neutrophil count, lymphocyte count, platelet count, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR), in anastomotic leakage during elective esophageal surgery. METHODS: This retrospective study included all patients who underwent esophagectomy for esophageal squamous cell carcinoma from 2016 to 2020 in our institution. The peripheral blood inflammatory indices were obtained on preoperative days 1-7 (PRD 1-7), and postoperative days 1-3 (POD 1-3) and 4-7 (POD 4-7). Univariate, multivariate logistic, and receiver operating characteristic curve analyses were conducted to evaluate the diagnostic value of these peripheral blood inflammatory indices. RESULTS: A total of 198 patients were included in the study, and 25 (13%) patients experienced anastomotic leakage. Multivariate analyses identified diet, neutrophil count, and PLR on POD 1-3, and NLR on POD 4-7 as independent factors associated with anastomotic leakage. Using the receiver operating characteristic curve, the variable with the best area under curve was a neutrophil cutoff count of 4.1 [0.737; 95% CI: 0.639-0.835], with a sensitivity and specificity of 60.0% and 66.5%, respectively. This was followed by an NLR cutoff value of 9.5 on POD 4-7 (0.628; 95% CI: 0.505-0.752) and a cutoff PLR value of 220.1 on POD 1-3 (0.643; 95% CI: 0.536-0.750). Diet showed a poor result on the receiver operating characteristic curve analysis. CONCLUSIONS: Neutrophil count and PLR on POD 1-3 and NLR on POD 4-7 were shown to have predictive value for anastomotic leakage in elective esophageal surgery.