KARS Mutations Impair Brain Myelination by Inducing Oligodendrocyte Deficiency: One Potential Mechanism and Improvement by Melatonin.

It is very crucial to investigate key molecules that are involved in myelination to gain an understanding of brain development and injury. We have reported for the first time that pathogenic variants p.R477H and p.P505S in KARS, which encodes lysyl-tRNA synthetase (LysRS), cause leukoencephalopathy with progressive cognitive impairment in humans. The role and action mechanisms of KARS in brain myelination during development are unknown. Here, we first generated Kars knock-in mouse models through the CRISPR-Cas9 system. Kars knock-in mice displayed significant cognitive deficits. These mice also showed significantly reduced myelin density and content, as well as significantly decreased myelin thickness during development. In addition, Kars mutations significantly induced oligodendrocyte differentiation arrest and reduction in the brain white matter of mice. Mechanically, oligodendrocytes' significantly imbalanced expression of differentiation regulators and increased capase-3-mediated apoptosis were observed in the brain white matter of Kars knock-in mice. Furthermore, Kars mutations significantly reduced the aminoacylation and steady-state level of mitochondrial tRNALys and decreased the protein expression of subunits of oxidative phosphorylation complexes in the brain white matter. Kars knock-in mice showed decreased activity of complex IV and significantly reduced ATP production and increased reactive oxygen species in the brain white matter. Significantly increased percentages of abnormal mitochondria and mitochondrion area were observed in the oligodendrocytes of Kars knock-in mouse brain. Finally, melatonin (a mitochondrion protectant) significantly attenuated mitochondrion and oligodendrocyte deficiency in the brain white matter of KarsR504H/P532S mice. The mice treated with melatonin also showed significantly restored myelination and cognitive function. Our study first establishes Kars knock-in mammal models of leukoencephalopathy and cognitive impairment and indicates important roles of KARS in the regulation of mitochondria, oligodendrocyte differentiation and survival, and myelination during brain development and application prospects of melatonin in KARS (or even aaRS)-related diseases.

Dioscin attenuates lupus nephritis in NZB/W F1 mice by decreasing NF-κB activation and NLRP3 inflammasome.

INTRODUCTION: Dioscin, a natural steroid saponin, has anticancer, anti-inflammatory, anti-hyperlipidemic, and glycemic capabilities. This study focused on dioscin roles and its related mechanisms in experimental lupus nephritis. MATERIALS AND METHODS: Lupus-prone NZB/W F1 mice were intragastrically administered with dioscin, prednisone or vehicle, and kidney, urine and blood samples were harvested after the mice were sacrificed. Proteinuria, blood urea nitrogen (BUN), creatinine, anti-dsDNA, IL-1ß, and IL-18 levels in serum as well as IFN-γ, IL-6, IL-17 and TNF-α levels in kidney tissues were assessed. Renal histopathology was examined through hematoxylin-eosin staining. IgG and C3 expression in kidney was evaluated using immunofluorescence staining. The number of glomerular F4/80-positive cells and NLRP3-positive cells was determined by immunohistochemical staining. The protein expression was examined by western blotting. RESULTS: Dioscin alleviated lupus nephritis in NZB/W F1 mice. Dioscin declined serum anti-dsDNA level, prevented deposition of immune complexes in renal glomeruli, and inhibited the inflammatory response and infiltration of macrophages into mouse kidneys. Dioscin inhibited NF-κB and NLRP3 inflammasome in NZB/W F1 mice. CONCLUSIONS: Dioscin ameliorates lupus nephritis through inhibition of NLRP3 inflammasome and NF-κB signaling.

Sodium selenite attenuates inflammatory response and oxidative stress injury by regulating the Nrf2/ARE pathway in contrast-induced acute kidney injury in rats.

BACKGROUND: Contrast-induced acute kidney injury (CI-AKI) is an acute renal complication that occurs after intravascular contrast agent administration. Sodium selenite (SS) is an inorganic source of Se and has potent antioxidant properties. This study intends to examine its anti-inflammatory and antioxidant effects in CI-AKI. METHODS: A rat CI-AKI model was established with the pretreatment of SS (0.35 mg/kg). Hematoxylin-eosin staining was employed for histopathological analysis of rat kidney specimens. Biochemical analysis was conducted for renal function detection. Tissue levels of oxidative stress-related markers were estimated. Reverse transcription-quantitative polymerase chain reaction revealed the mRNA levels of proinflammatory cytokines. Western blotting showed the Nrf2 signaling-related protein expression in the rat kidney. RESULTS: SS administration alleviated the renal pathological changes and reduced the serum levels of serum creatinine, blood urea nitrogen, neutrophil gelatinase-associated lipocalin, cystatin C, and urinary level of kidney injury molecule-1 in CI-AKI rats. SS attenuated oxidative stress and inflammatory response in CI-AKI rat kidney tissues. SS activated the Nrf2 signaling transduction in the renal tissues of rats with CI-AKI. CONCLUSION: SS ameliorates CI-AKI in rats by reducing oxidative stress and inflammation via the Nrf2 signaling.

Dynamics of carbon sequestration in vegetation affected by large-scale surface coal mining and subsequent restoration.

Surface coal development activities include mining and ecological restoration, which significantly impact regional carbon sinks. Quantifying the dynamic impacts on carbon sequestration in vegetation (VCS) during coal development activities has been challenging. Here, we provided a novel approach to assess the dynamics of VCS affected by large-scale surface coal mining and subsequent restoration. This approach effectively overcomes the limitations imposed by the lack of finer scale and long-time series data through scale transformation. We found that mining activities directly decreased VCS by 384.63 Gg CO2, while restoration activities directly increased 192.51 Gg CO2 between 2001 and 2022. As of 2022, the deficit in VCS at the mining areas still had 1966.7 Gg CO2. The study highlights that complete restoration requires compensating not only for the loss in the year of destruction but also for the ongoing accumulation of losses throughout the mining lifecycle. The findings deepen insights into the intricate relationship between coal resource development and ecological environmental protection.

Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first line treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma: RATIONALE-305 randomised, double blind, phase 3 trial.

OBJECTIVE: To evaluate the efficacy and safety of tislelizumab added to chemotherapy as first line (primary) treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma compared with placebo plus chemotherapy. DESIGN: Randomised, double blind, placebo controlled, phase 3 study. SETTING: 146 medical centres across Asia, Europe, and North America, between 13 December 2018 and 28 February 2023. PARTICIPANTS: 1657 patients aged ≥18 years with human epidermal growth factor receptor 2 negative locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma, regardless of programmed death-ligand 1 (PD-L1) expression status, who had not received systemic anticancer therapy for advanced disease. INTERVENTIONS: Patients were randomly (1:1) assigned to receive either tislelizumab 200 mg or placebo intravenously every three weeks in combination with chemotherapy (investigator's choice of oxaliplatin and capecitabine, or cisplatin and 5-fluorouracil) and stratified by region, PD-L1 expression, presence or absence of peritoneal metastases, and investigator's choice of chemotherapy. Treatment continued until disease progression or unacceptable toxicity. MAIN OUTCOME MEASURES: The primary endpoint was overall survival, both in patients with a PD-L1 tumour area positivity (TAP) score of ≥5% and in all randomised patients. Safety was assessed in all those who received at least one dose of study treatment. RESULTS: Of 1657 patients screened between 13 December 2018 and 9 February 2021, 660 were ineligible due to not meeting the eligibility criteria, withdrawal of consent, adverse events, or other reasons. Overall, 997 were randomly assigned to receive tislelizumab plus chemotherapy (n=501) or placebo plus chemotherapy (n=496). Tislelizumab plus chemotherapy showed statistically significant improvements in overall survival versus placebo plus chemotherapy in patients with a PD-L1 TAP score of ≥5% (median 17.2 months v 12.6 months; hazard ratio 0.74 (95% confidence interval 0.59 to 0.94); P=0.006 (interim analysis)) and in all randomised patients (median 15.0 months v 12.9 months; hazard ratio 0.80 (0.70 to 0.92); P=0.001 (final analysis)). Grade 3 or worse treatment related adverse events were observed in 54% (268/498) of patients in the tislelizumab plus chemotherapy arm versus 50% (246/494) in the placebo plus chemotherapy arm. CONCLUSIONS: Tislelizumab added to chemotherapy as primary treatment for advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma provided superior overall survival with a manageable safety profile versus placebo plus chemotherapy in patients with a PD-L1 TAP score of ≥5%, and in all randomised patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT03777657.

Insulin-like growth factor 1 knockdown attenuates high glucose-induced podocyte injury by promoting the JAK2/STAT signalling-mediated autophagy.

PURPOSE: Podocyte injury plays a crucial role in the development of diabetic nephropathy (DN). A high serum level of insulin-like growth factor 1 (IGF-1) has been observed in patients with DN. This paper is to study the role and mechanism of IGF-1 in high glucose (HG)-induced podocyte injury. METHODS: Mouse podocytes MPC-5 were treated with HG to establish a DN model in vitro. db/db diabetic mice and db/m nondiabetic mice were used to evaluate the IGF-1 role in vivo. Western blotting was used for measuring protein levels of IGF-1 receptor, Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathway-related markers, podocyte markers podocin and nephrin, apoptosis- and autophagy-related markers in MPC-5 cells. Immunofluorescence staining was implemented for measuring the expression of nephrin and the autophagy marker LC3. Flow cytometry was used for detecting podocyte apoptosis. RESULTS: IGF-1 expression was increased in HG-stimulated MPC-5 cells and the kidney of db/db diabetic mice compared with corresponding controls. Knocking down IGF-1 downregulated IGF-1R and inhibited JAK2/STAT signalling pathway in HG-treated MPC-5 cells and db/db diabetic mice. IGF-1 silencing attenuated HG-induced podocyte injury, apoptosis and reduction in autophagy. Activating the JAK2/STAT signalling pathway or inhibiting autophagy reversed the effects of IGF-1 silencing on HG-treated MPC-5 cells. CONCLUSION: Knocking down IGF-1 alleviates HG-induced podocyte injury and apoptosis by inactivating the JAK2/STAT signalling pathway and enhancing autophagy.

Multifunctional fish-skin collagen-based hydrogel sealant with dual-dynamic-bond cross-linked for rapid hemostasis and accelerated wound healing.

Collagen (COL) is the most widespread functional protein. Designing and developing dual-dynamic-bond cross-linked COL adhesive hydrogel sealants with multifunctional is highly advantageous for achieving a superior wound closure effect and hemostasis. In this study, we developed hybrid hydrogels consisting of fish-skin COL, oxidized sodium alginate (OSA), borax and polyvinyl alcohol (PVA) to enhance full-thickness wound healing. The hydrogels were furnished with first-rate self-healing capabilities through the dual-dynamic-bond cross-linking of dynamic Schiff base bonds (COL-OSA) and diol boric acid bonds (OSA-borax) with reversible breakage and re-formation. Moreover, the incorporation of PVA stimulated the formation of hydrogen bonds in the system, bolstering the stability of the hydrogel framework. The prepared hydrogel manifests self-healing, injectability, multifunctional adhesiveness and biodegradability. In vivo assessment of the hemostatic capacity of COSP20 hydrogel was superior to gauze both in the mice liver injury model and mice tail amputation model. In addition, a full-thickness skin wound model in mice revealed that the COSP20 hydrogel facilitated faster wound closure by accelerating reepithelialization, COL deposition and angiogenesis. These findings illustrate the potential of hybrid fish-skin COL-based hydrogels to enhance wound healing and promote rapid tissue repair, and provide new possibilities for the effective utilization of marine fishery resources.

Aurantio-obtusin exerts an anti-inflammatory effect on acute kidney injury by inhibiting NF-κB pathway.

Acute kidney injury (AKI) is one of the major complications of sepsis. Aurantio-obtusin (AO) is an anthraquinone compound with antioxidant and anti-inflammatory activities. This study was developed to concentrate on the role and mechanism of AO in sepsis-induced AKI. Lipopolysaccharide (LPS)-stimulated human renal proximal tubular epithelial cells (HK-2) and BALB/c mice receiving cecal ligation and puncture (CLP) surgery were used to establish in vitro cell model and in vivo mouse model. HK-2 cell viability was measured using MTT assays. Histological alterations of mouse renal tissues were analyzed via hematoxylin and eosin staining. Renal function of mice was assessed by measuring the levels of serum creatinine (SCr) and blood urea nitrogen (BUN). The concentrations of pro-inflammatory cytokines in HK-2 cells and serum samples of mice were detected using corresponding ELISA kits. Protein levels of factors associated with nuclear factor kappa-B (NF-κB) pathway were measured in HK-2 cells and renal tissues by Western blotting. AO exerted no cytotoxic effect on HK-2 cells and AO dose-dependently rescued LPS-induced decrease in HK-2 cell viability. The concentrations of pro-inflammatory cytokines were increased in response to LPS or CLP treatment, and the alterations were reversed by AO treatment. For in vivo experiments, AO markedly ameliorated renal injury and reduced high levels of SCr and BUN in mice underwent CLP operation. In addition, AO administration inhibited the activation of NF-κB signaling pathway in vitro and in vivo. In conclusion, AO alleviates septic AKI by suppressing inflammatory responses through inhibiting the NF-κB pathway.

Efficacy of perinatal pharmacotherapeutic actions for survival of very preterm newborn rabbits at 26-day gestation.

Investigation of the pathophysiology of lung impairment and protection in very preterm neonates at birth requires adequate experimental models. This study aimed to elucidate the efficacy and mechanism of perinatal pharmacotherapeutic action in postnatal survival of very preterm rabbits. Pregnant New Zealand White rabbits on 25-day gestation (term 31 days) were given dexamethasone (D), or sham injection as control (C), and cesarean delivered 24 hours later on day 26. Newborns were anesthetized, intratracheally intubated, randomly received either saline or porcine surfactant (S), allocated to four groups (C, S, D, and DS), and ventilated with low tidal volume. Under the identical protocol, another four groups were added with nitric oxide (N) inhalation (CN, SN, DN, and DSN). Survival length, lung mechanics, histopathology, and pathobiology of lung tissue were measured for benefits and injury patterns. DSN had the longest median survival time (ST50, 10.3 h), whereas C had the shortest (3.5 h), with remaining groups in-between. The survival was mainly benefited by S, when additive effects with D and/or N were discernible, by improved lung mechanics and alveolar aeration, ameliorated lung injury severity and pneumothorax, and augmented lung phospholipid pools, with DSN being the most optimal. Variable mRNA expression profiles of alveolar epithelia-associated cytokines and inflammatory mediators further characterized injury and response patterns as phenotyping conditioned in pharmacotherapeutic actions. In conclusion, the combined regimens of perinatal medications achieved remarkable survival in very preterm rabbits with lung protective ventilation strategy, offering a unique model in investigation of very preterm birth-associated respiratory physiology and morbidities.NEW & NOTEWORTHY By establishing a very preterm rabbit model with 26-day gestation (term 31 days), optimal survival length for 50% of animals in groups was achieved by comparing regimens of combined antenatal glucocorticoids, postnatal surfactant and inhaled nitric oxide, with a low tidal volume ventilation strategy. The efficacies of pharmacotherapeutic action were associated with significantly improved lung mechanics, ameliorated lung injury and pneumothorax, and enhanced surfactant phospholipid metabolism, along with variable mRNA expression profiles characterizing the response patterns.

Efficacy of synthetic surfactant (CHF5633) bolus and/or lavage in meconium-induced lung injury in ventilated newborn rabbits.

BACKGROUND: The pathogenesis of neonatal meconium aspiration syndrome (MAS) involves meconium-induced lung inflammation and surfactant inactivation. Bronchoalveolar lavage (BAL) with diluted surfactant facilitates the removal of meconium. CHF5633, one of the most promising synthetic surfactants, is effective in neonatal respiratory distress syndrome. Here we investigated its efficacy via BAL in an experimental MAS model. METHODS: Experimental MAS was induced at birth in near-term newborn rabbits by intratracheal instillation of reconstituted human meconium. First, undiluted CHF5633 was compared with a porcine-derived surfactant (Poractant alfa) via intratracheal bolus (200 mg/kg). Second, the efficacy of BAL with diluted CHF5633 (5 mg/mL, 20 ml/kg) alone, or followed by undiluted boluses (100 or 300 mg/kg), was investigated. RESULTS: Meconium instillation caused severe lung injury, reduced endogenous surfactant pool, and poor survival. CHF5633 had similar benefits in improving survival and alleviating lung injury as Poractant alfa. CHF5633 BAL plus higher boluses exerted better effects than BAL or bolus alone in lung injury alleviation by reversing phospholipid pools and mitigating proinflammatory cytokine mRNA expression, without fluid retention and function deterioration. CONCLUSIONS: CHF5633 improved survival and alleviated meconium-induced lung injury, the same as Poractant alfa. CHF5633 BAL plus boluses was the optimal modality, which warrants further clinical investigation. IMPACT: To explore the efficacy of a synthetic surfactant, CHF5633, in neonatal lung protection comparing with Poractant alfa in a near-term newborn rabbit model with meconium-induced lung injury. Similar effects on improving survival and alleviating lung injury were found between CHF5633 and Poractant alfa. Optimal therapeutic effects were identified from the diluted CHF5633 bronchoalveolar lavage followed by its undiluted bolus instillation compared to the lavage or bolus alone regimens. Animals with CHF5633 lavage plus bolus regimen exerted neither substantial lung fluid retention nor lung mechanics deterioration but a trend of higher pulmonary surfactant-associated phospholipid pools.

Unmixing the coupling influence from driving factors on vegetation changes considering spatio-temporal heterogeneity in mining areas: a case study in Xilinhot, Inner Mongolia, China.

Considering the spatio-temporal heterogeneity, this study resolved the coupling influence of a variety of driving factors on vegetation changes in mining areas and discovered the influencing characteristics of the respective driving factors, especially mining activities. First, the spatio-temporal characteristics of FVC (fractional vegetation cover) variation were analyzed in the Sheng-Li mining area. Second, the quantitative relationships among the natural factors (temperature, precipitation, and elevation), artificial factors (mining activities, urban activities), and FVC were constructed by GTWR (geographically and temporally weighted regression) to quantify the contribution of each factor to the change in FVC. Third, the influencing characteristics of the respective driving factors, especially mining activities, were analyzed and summarized. The results show that (1) the FVC change was mainly influenced by natural factors in the areas far from mines and towns and artificial factors in the areas close to mines and towns. (2) The contribution of mining activities to vegetation change (C-Mine) was spatially characterized by two features: (a) distance attenuation characteristics: C-Mine showed logarithmic decrement with distance; (b) directional heterogeneity: C-Mine varied significantly in different directions. In particular, there was a high C-Mine area located near multiple mining areas, and the range of this area shifted to include the mine with more production over time. Overall, unmixing the coupling influence from driving factors with spatio-temporal heterogeneity and achieving a quantitative description of the influencing characteristics in mining areas were the main contributions of this study. The quantification methods and results in this paper provide important support for decision-making on ecological protection and restoration in mining areas.

Outcome of neonatal hypoxemic respiratory failure: a livebirth population-based retrospective survey.

BACKGROUND: To explore the prevalence, outcome and perinatal risks of neonatal hypoxemic respiratory failure (NRF) in a survey of all livebirths from a regional network of perinatal-neonatal care during the transition period after 5-year universal health insurance implemented in China. METHODS: Clinical data of all neonatal respiratory morbidities in Huai'an were retrospectively collected in the regional perinatal network database of all livebirths as vital statistics in 2015. NRF was defined as hypoxemia requiring continuous positive airway pressure (CPAP) and/or mechanical ventilation (MV) for at least 24 h. Mortality risks of antenatal and perinatal morbidities, major respiratory therapies and complications were analyzed by multivariable logistic regression model. RESULTS: There were 788 NRF cases identified in 9.9% (7960) hospitalized, or 13.3‰ (59056) livebirths, in which 6.7% received intensive care and 93.0% critical care. The major underlying morbidities were respiratory distress syndrome (RDS, 36.4%) and pneumonia/sepsis (35.3%), treated mainly by CPAP, MV and surfactant. Significantly improved outcomes by surfactant in RDS were in patients with birthweight (BW) < 1500 g or gestational age (GA) < 32 weeks. The overall mortality rate in NRF was 18.4% whereas for those of BW < 1000 g and GA < 28 weeks, 70% and 54%, respectively. The multivariable regression analysis showed the highest odds for NRF death among meconium aspiration syndrome, congenital anomalies, BW < 1500 g and necrotizing enterocolitis, whereas born in level III hospitals, cesarean delivery, CPAP and MV were associated with markedly reduced death odds. CONCLUSIONS: The salient findings with associated risk estimates reflected efficiency of respiratory support as critical care in a prefectural regional network infrastructure for annual livebirths in 5.6 million inhabitants. It implicated the representativeness of contemporaneous perinatal-neonatal care standard at medium to medium-high level, in one/fourth of the population of China, aiming at saving more life of very critical and preterm infants for better survival.

[Analysis of risk factors of major adverse kidney events within 30 days in patients with acute pancreatitis].

OBJECTIVE: To analyze the risk factors of major adverse kidney events within 30 days (MAKE30) in patients with acute pancreatitis (AP). METHODS: A retrospective cohort study was conducted. A total of 162 patients who were first diagnosed with AP in the First Affiliated Hospital of Soochow University from June 2019 to June 2021 and the onset time was less than 72 hours were enrolled. Patients were divided into MAKE30 group and non-MAKE30 group according to the occurrence of MAKE30 after hospitalization. MAKE30 was defined as death from any cause, new renal replacement therapy (RRT), and persistent renal insufficiency (PRD). The clinical data of the two groups at admission were compared. The independent risk factors of MAKE30 were analyzed by multivariate Logistic regression method, and a regression equation was established as a quantitative prediction model of MAKE30. Receiver operator characteristic curve (ROC curve) was drawn to analyze the prediction of the quantitative prediction model value. RESULTS: All 162 patients were included in the final analysis, including 32 in the MAKE30 group and 130 in the non-MAKE30 group. Univariate analysis showed that compared with the non-MAKE30 group, the body mass index (BMI), the proportion of severe AP, and the acute physiology and chronic health evaluation II (APACHE II) score, the sequential organ failure assessment (SOFA) score, blood urea nitrogen (BUN), serum creatinine (SCr), C-reactive protein (CRP), HCO3-, Cl- levels and the proportion of hyperchloremia at admission in the MAKE30 group were significantly increased. Multivariate Logistic regression analysis showed that APACHE II score at admission [odds ratio (OR) = 1.659, 95% confidence interval (95%CI) was 1.426-1.956, P = 0.009], SOFA score (OR = 1.501, 95%CI was 1.236-1.840, P = 0.014) and hyperchloremia (OR = 1.858, 95%CI was 1.564-2.231, P = 0.004) were independent risk factors for MAKE30 in AP patients. The MAKE30 regression equation was established by the above risk factors [Logit(P) = 0.063+0.525×APACHE II score+0.328×SOFA score+0.895×hyperchloremia], which was used as the MAKE30 quantitative prediction model. ROC curve analysis showed that the area under the ROC curve (AUC) of the model for predicting MAKE30 was 0.846 (95%CI was 0.774-0.923, P = 0.001). The patients were divided into two subgroups with hyperchloremia (Cl- ≥ 110 mmol/L, n = 19) and non-hyperchloremia (Cl- < 110 mmol/L, n = 143) according to the blood Cl- level at admission. The incidence of MAKE30 and acute kidney injury (AKI) in the hyperchloremia group was significantly increased (MAKE30: 68.4% vs. 13.3%, AKI: 89.5% vs. 43.4%), and the levels of BUN and SCr at admission were significantly increased [BUN (mmol/L): 9.3±2.5 vs. 5.9±1.1, SCr (µmol/L): 162.3±26.4 vs. 78.6±9.2], the total length of hospital stay and length of intensive care unit (ICU) stay were significantly longer [total length of hospital stay (days): 10.2±1.6 vs. 5.6±1.2, length of ICU stay (days): 6.2±1.0 vs. 3.1±0.6], the cumulative intravenous infusion volume increased significantly at 48 hours and 72 hours (mL: 7 235.9±1 025.3 vs. 5 659.6±956.7 at 48 hours, 11 052.6±1 659.8 vs. 7 156.9±1 052.4 at 72 hours), differences were statistically significant (all P < 0.01). CONCLUSIONS: MAKE30 can be used as an important indicator to evaluate the short-term clinical prognosis of AP patients. APACHE II score, SOFA score and hyperchloremia at admission are the main risk factors. The risk model of MAKE30 based on these three indicators has good predictive performance. AP patients with hyperchloremia are at high risk of developing MAKE30, which should be highly regarded in clinical practice.

The combination of gene hyperamplification and PD-L1 expression as a biomarker for the clinical benefit of tislelizumab in gastric/gastroesophageal junction adenocarcinoma.

BACKGROUND: In solid tumor Phase 1/2 trials (NCT02407990; NCT04068519), tislelizumab demonstrated clinical benefit, including in advanced gastroesophageal adenocarcinoma (GEA). However, the majority of patients with GEA did not respond, highlighting the need to understand mechanisms of resistance and identify predictive biomarkers for response. METHODS: All tislelizumab-treated patients with GEA from the Phase 1/2 trials were included (N = 105). Programmed death-ligand 1 (PD-L1) expression (Tumor Area Positivity [TAP] ≥ 5%), interferon gamma (IFNγ)-related gene signature, gene expression profile, tumor mutational burden (TMB), and gene hyperamplification (HA) were analyzed for correlation with tislelizumab. RESULTS: A moderate association was observed between PD-L1 TAP ≥ 5%, IFNγ gene signature, TMB-high and efficacy. A potential correlation between hyperamplification (HA +) and worse outcomes with programmed cell death protein 1 (PD-1) inhibition was identified. Hyperamplified genes were mainly enriched in cancer progression pathways, including cell cycle and RTK-RAS-PI3K pathways. Joint PD-L1 TAP ≥ 5% and lack of hyperamplification showed the most favorable benefit with an objective response rate of 29.4%, and median progression-free survival and overall survival of 4.1 and 14.7 months, respectively. Tumors with TAP ≥ 5% and HA - had inflamed immune signatures with increased immune cell infiltration, enhanced anti-tumor cytotoxic activity and antigen presentation signatures. Findings were validated in two independent gastric and gastrointestinal cancer cohorts treated with immune checkpoint inhibitors. CONCLUSIONS: In GEA, PD-L1 positivity, IFNγ-related gene signature and TMB-high status were positively associated with tislelizumab clinical benefit, whereas HA was associated with worse clinical outcomes. Combining PD-L1 positivity and HA - may help identify patients more likely to benefit from PD-1 blockade.

Comparative study on characteristics of mandarin peel extracts by biological processing.

Mandarin peel is a by-product from mandarin canning industry containing multiple functional substances with useful properties such as antibacterial and antioxidant activities. To evaluate the effect of bioprocessing, fresh mandarin peels were fermented by Rhizopus stolonifer JP13 for 4 days and then the peels' antioxidant and antimicrobial activities were tested. The flavonoiuds, hesperidin and VC contents in dry peels were also determined. The data showed that the fermented mandarin peels had promoted antibacterial activity against Escherichia coli, Staphylococcus aureus, Aspergillus flavus, and Candida albicans. An increased scavenging effect on free radicals, with 73.0% of·OH scavenging activities were obtained when compared with fresh mandarin peels. We also observed a significant increase on content of flavonoid (334%) and hesperindin (253.7%), a reduced scavenging effect on O2- free radicals (13.94%), and a decrease content of VC (13.7%). The presaging of mandarin peels by Rhizopus stolonifer JP13 strain will promote the functional activities of mandarin peels and accelerate the process of manufacture Citri Reticulatae Pericarpium.

A versatile Y shaped DNA nanostructure for simple, rapid and one-step detection of mycotoxins.

A versatile Y shaped DNA nanostructure has been developed for simple, rapid and one-step simultaneous detection aflatoxin B1 (AFB1) and ochratoxin A (OTA). Y shaped duplex DNA arms was formed with two DNA tweezer at the ends. The aptamer sequence at the third end can bind to its target mycotoxins with strong affinity and then release the two DNA fragments. The released DNA fragments can open the DNA tweezers at the ends of Y shaped DNA arm. The amounts of AFB1 and OTA can be quantitative detection through the recovery of the fluorescent intensities. This strategy is simple and rapid with self-powered DNA hybridization reaction to control the "open" of Y shaped DNA tweezers. Furthermore, it can be finished in 60 min with only one-step of operation. The linear range of AFB1 was from 0.5 to 200 ng/mL (R2 = 0.995) and linear relationship of OTA was obtained from 4 to 300 ng/mL (R2 = 0.990). It also has been successfully applied for mycotoxins detection in real food samples. Importantly, the target mycotoxins can be extended to others by simply replacing the corresponding aptamer sequences.

Factors associated with glycemic variability in children with type 1 diabetes mellitus based on flash glucose monitoring system. / 基于扫描式葡萄糖监测系统的儿童1åž‹ç³–å°¿ç— æ‚£è€ è¡€ç³–æ³¢åŠ¨çš„å½±å“å› ç´ .

OBJECTIVES: Patients with classical type 1 diabetes mellitus (T1DM) require lifelong dependence on exogenous insulin therapy due to pancreatic beta-cell destruction and absolute insulin deficiency. T1DM accounts for about 90% of children with diabetes in China, with a rapid increase in incidence and a younger-age trend. Epidemiological studies have shown that the overall glycated haemoglobin (HbA1c) and compliance rate are low in Chinese children with T1DM. Optimal glucose control is the key for diabetes treatment, and maintaining blood glucose within the target range can prevent or delay chronic vascular complications in patients with T1DM. Therefore, this study aims to investigate the glycemic control of children with T1DM from Hunan and Henan Province with flash glucose monitoring system (FGMS), and to explore factors associated with glycemic variability. METHODS: A total of 215 children with T1DM under 14 years old were enrolled continuously in 16 hospitals from August 2017 to August 2020. All subjects wore a FGMS device to collect glucose data. Correlation of HbA1c, duration of diabetes, or glucose scan rates with glycemic variability was analyzed. Glucose variability was compared according to the duration of diabetes, HbA1c, glucose scan rates and insulin schema. RESULTS: HbA1c and duration of diabetes were positively correlated with mean blood glucose, standard deviation of glucose, mean amplitude of glucose excursions (MAGE), and coefficient of variation (CV) of glucose (all P<0.01). The glucose scan rates during FGMS wearing was significantly positively correlated with time in range (TIR) (P=0.001) and negatively correlated with MAGE and mean duration of hypoglycemia (all P<0.01). Children with duration ≤1 year had lower time below range (TBR) and MAGE when compared with those with duration >1 year (all P<0.05). TIR and TBR in patients with HbA1c ≤7.5% were higher (TIR: 65% vs 45%, TBR: 5% vs 4%, P<0.05), MAGE was lower (7.0 mmol/L vs 9.4 mmol/L, P<0.001) than those in HbA1c >7.5% group. Compared to the multiple daily insulin injections group, TIR was higher (60% vs 52%, P=0.006), MAGE was lower (P=0.006) in the continuous subcutaneous insulin infusion group. HbA1c was lower in the high scan rates (≥14 times/d) group (7.4% vs 8.0%, P=0.046), TIR was significantly higher (58% vs 47%, P<0.001), and MAGE was lower (P<0.001) than those in the low scan rate (<14 times/d) group. CONCLUSIONS: The overall glycemic control of T1DM patients under 14 years old in Hunan and Henan Province is under a high risk of hypoglycemia and great glycemic variability. Shorter duration of diabetes, targeted HbA1c, higher glucose scan rates, and CSII are associated with less glycemic variability.

Perinatal Risks of Neonatal and Infant Mortalities in a Sub-provincial Region of China: A Livebirth Population-based Cohort Study.

BACKGROUND: Current vital statistics of birth population and neonatal outcome in China lacked information and definition of deaths at delivery and during hospitalization, especially for extreme preterm (EPT) birth. This study aims to delineate the prevalence of neonatal hospitalization, neonatal and infant mortality rates (NMR, IMR) and associated perinatal risks based on all livebirths in Huai'an, an evolving sub-provincial region in eastern China. METHODS: This retrospective cohort study established a comprehensive database linking information of whole regional livebirths and neonatal hospitalization in 2015, including deaths at delivery and EPT livebirths. The primary outcomes were NMR and IMR stratified by gestational age (GA) and birthweight (BW) with 95% confidence intervals. Causes of the neonatal and infant deaths were categorized according to the International Statistical Classification of Diseases 10th version, and population attributable fractions of GA and BW strata were analyzed. Perinatal risks of infant mortalities in continuum periods were estimated by Cox regression models. RESULTS: Among the whole livebirth population (59056), 7960 were hospitalized (prevalence 13.5%), with 168 (2.8‰) in-hospital deaths. The NMR was 3.6 (3.2, 4.1)‰ and IMR 4.9 (1.4, 4.5)‰, with additionally 35 (0.6‰) deaths at delivery. The major causes of infant deaths were perinatal conditions (2.6‰, mainly preterm-related), congenital anomalies (1.5‰), sudden unexpected death in infancy (0.6‰) and other causes (0.2‰). The deaths caused by preterm and low BW (LBW) accounted for 50% and 40% of NMR and IMR, with 20-30% contributed by EPT or extremely LBW, respectively. Multivariable Cox regression analysis revealed that peripartum factors and LBW strata had strong association with early- and late-neonatal deaths, whereas those of GA < 28 weeks were highly associated with postneonatal deaths. Congenital anomalies and neonatal hospitalization remained high death risks over the entire infancy, whereas maternal co-morbidities/complications were modestly associated with neonatal but not postneonatal infant mortality. CONCLUSIONS: The NMR, IMR, major causes of deaths and associated perinatal risks in continuum periods of infancy, denote the status and quality improvement of the regional perinatal-neonatal care associated with socioeconomic development. The study concept, applicability and representativeness may be validated in other evolving regions or countries for genuine comparison and better maternal-infant healthcare.

Prevalence of major morbidities and outcome of all hospitalized neonates. A retrospective cohort study of Huai'an neonatal survivals.

BACKGROUND: Reliable data for causal implication of neonatal survival in China are lacking. We assumed that by analyzing surviving data of in-hospital neonatal care based on all livebirths in Huai'an, prevalence of neonatal morbidity, mortality and causal relations may be derived comprehensively. MATERIALS AND METHODS: Data of all regionally hospitalized neonates were retrospectively linked with corresponding whole livebirths (59,056) in 2015 as a cohort. Diagnoses of diseases and causes of deaths were redefined and categorized. Disease patterns, prevalence of morbidities, case-fatality rate (CFR), and cause-specific mortality rate (CSMR) referring to livebirths were presented. Perinatal and disease-specific risks of death were estimated by multivariable logistic regression. RESULTS: In 7,960 (134.8‰) hospitalized patients, 168 (2.1%) died in hospital (2.85‰ of livebirths). Prevalence of major morbidities were 76.8‰ hyperbilirubinemia, 57.4‰ pneumonia, 32.7‰ intraventricular hemorrhage, 20.7‰ sepsis, 20.2‰ birth asphyxia, 9.69‰ congenital anomalies (CA), and 5.30‰ respiratory distress syndrome (RDS). The CFR (CSMR) of major diseases were 30.4% (0.12‰) meconium aspiration syndrome, 17.6% (0.22‰) necrotizing enterocolitis, 14.1% (0.75‰) RDS, 9.09% (0.88‰) CA, 5.26% (0.07‰) bronchopulmonary dysplasia, 1.71% (0.36‰) sepsis and 1.51% (0.31‰) asphyxia. Overall mortality rates were 4.6% and 6.8% in the preterm and low birthweight, and >50% in those of <28 week gestation or <1000 g birthweight, respectively. Mortality risks associated with the perinatal and neonatal morbidities were markedly declined with variable magnitude by multivariable regression models. CONCLUSIONS: The in-hospital neonatal survival datafile, depicted as the prevalence of major morbidities and CSMR of livebirth population in Huai'an, denoted overall and specific quality and efficiency of the perinatal-neonatal care system. Its concept and methodology should be relevant, and outcome extrapolated, to other countries or domestic regions, with similar socioeconomic development.

Impact of flash glucose monitoring on glycemic control varies with the age and residual ß-cell function of patients with type 1 diabetes mellitus.

AIMS/INTRODUCTION: We aimed to explore the clinical factors associated with glycemic variability (GV) assessed with flash glucose monitoring (FGM), and investigate the impact of FGM on glycemic control among Chinese type 1 diabetes mellitus patients in a real-life clinical setting. MATERIALS AND METHODS: A total of 171 patients were included. GV was assessed from FGM data. A total of 110 patients wore FGM continuously for 6 months (longitudinal cohort). Hemoglobin A1c (HbA1c), fasting and 2-h postprandial C-peptide, and glucose profiles were collected. Changes in HbA1c and glycemic parameters were assessed during a 6-month FGM period. RESULTS: Individuals with high residual C-peptide (HRCP; 2-h postprandial C-peptide >200 pmol/L) had less GV than patients with low residual C-peptide ( 2-h postprandial C-peptide ≤200 pmol/L; P < 0.001). In the longitudinal cohort (n = 110), HbA1c and mean glucose decreased, time in range (TIR) increased during the follow-up period (P < 0.05). The 110 patients were further divided into age and residual C-peptide subgroups: (i) HbA1c and mean glucose were reduced significantly only in the subgroup aged ≤14 years during the follow-up period, whereas time below range also increased in this subgroup at 3 months (P = 0.047); and (ii) HbA1c improved in the HRCP subgroup at 3 and 6 months (P < 0.05). The mean glucose decreased and TIR improved significantly in the low residual C-peptide subgroup; however, TIR was still lower and time below range was higher than those of the HRCP subgroup at all time points (P < 0.05). CONCLUSIONS: HRCP was associated with less GV. FGM wearing significantly reduced HbA1c, especially in pediatric patients and those with HRCP. Additionally, the mean glucose and TIR were also found to improve.