Short-term usage of proton pump inhibitors during admission was associated with increased risk of rehospitalization in critically ill patients with myocardial infarction: a cohort study.

PURPOSE: Previous studies showed that long-term use of proton pump inhibitors (PPIs) was associated with cardiovascular events. However, the impact of short-term PPI exposure on intensive care unit (ICU) patients with myocardial infarction (MI) remains largely unknown. This study aims to determine the precise correlation between short-term PPI usage during hospitalization and prognostic outcomes of ICU-admitted MI patients using Medical Information Mart for Intensive Care IV database (MIMIC-IV). METHODS: Propensity score matching (PSM) was applied to adjust confounding factors. The primary study outcome was rehospitalization with mortality and length of stay as secondary outcomes. Binary logistic, multivariable Cox, and linear regression analyses were employed to estimate the impact of short-term PPI exposure on ICU-admitted MI patients. RESULTS: A total of 7249 patients were included, involving 3628 PPI users and 3621 non-PPI users. After PSM, 2687 pairs of patients were matched. The results demonstrated a significant association between PPI exposure and increased risk of rehospitalization for MI in both univariate and multivariate [odds ratio (OR) = 1.157, 95% confidence interval (CI) 1.020-1.313] analyses through logistic regression after PSM. Furthermore, this risk was also observed in patients using PPIs > 7 days, despite decreased risk of all-cause mortality among these patients. It was also found that pantoprazole increased the risk of rehospitalization, whereas omeprazole did not. CONCLUSION: Short-term PPI usage during hospitalization was still associated with higher risk of rehospitalization for MI in ICU-admitted MI patients. Furthermore, omeprazole might be superior to pantoprazole regarding the risk of rehospitalization in ICU-admitted MI patients.

Plant-derived natural compounds: A new frontier in inducing immunogenic cell death for cancer treatment.

Immunogenic cell death (ICD) can activate adaptive immune response in the host with normal immune system. Some synthetic chemotherapeutic drugs and natural compounds have shown promising results in cancer treatment by triggering the release of damage-associated molecules (DAMPs) to trigger ICD. However, most chemotherapeutic drugs exhibit non-selective cytotoxicity and may also induce and promote metastasis, thereby significantly reducing their clinical efficacy. Among the natural compounds that can induce ICD, plant-derived compounds account for the largest proportion, which are of increasing value in the treatment of cancer. Understanding which plant-derived natural compounds can induce ICD and how they induce ICD is crucial for developing strategies to improve chemotherapy outcomes. In this review, we focus on the recent findings regarding plant-derived natural compounds that induce ICD according to the classification of flavonoids, alkaloids, glycosides, terpenoids and discuss the potential mechanisms including endoplasmic reticulum (ER) stress, DNA damage, apoptosis, necroptosis autophagy, ferroptosis. In addition, plant-derived natural compounds that can enhance the ICD induction ability of conventional therapies for cancer treatment is also elaborated. The rational use of plant-derived natural compounds to induce ICD is helpful for the development of new cancer treatment methods.

circUQCRC2 promotes asthma progression in children by activating the VEGFA/NF-κB pathway by targeting miR-381-3p.

This study targeted to explore circUQCRC2's role and mechanism in childhood asthma. A mouse model of ovalbumin-induced asthma was established to evaluate the effects of circUQCRC2 on childhood asthma in terms of oxidative stress, inflammation, and collagen deposition. The effects of circUQCRC2 on platelet-derived growth factor-BB (PDGF-BB)-induced smooth muscle cells (SMCs) were evaluated, the downstream mRNA of miRNA and its associated pathways were predicted and validated, and their effects on asthmatic mice were evaluated. circUQCRC2 levels were upregulated in bronchoalveolar lavage fluid of asthmatic mice and PDGF-BB-treated SMCs. Depleting circUQCRC2 alleviated tissue damage in asthmatic mice, improved inflammatory levels and oxidative stress in asthmatic mice and PDGF-BB-treated SMC, inhibited malignant proliferation and migration of SMCs, and improved airway remodeling. Mechanistically, circUQCRC2 regulated VEGFA expression through miR-381-3p and activated the NF-κB cascade. circUQCRC2 knockdown inactivated the NF-κB cascade by modulating the miR-381-3p/VEGFA axis. Promoting circUQCRC2 stimulates asthma development by activating the miR-381-3p/VEGFA/NF-κB cascade. Therefore, knocking down circUQCRC2 or overexpressing miR-381-3p offers a new approach to treating childhood asthma.

Integrated cell wall and transcriptomic analysis revealed the mechanism underlying zinc-induced alleviation of cadmium toxicity in Cosmos bipinnatus.

Plant growth is severely harmed by cadmium (Cd) contamination, while the addition of zinc (Zn) can reduce the toxic effects of Cd. However, the interaction between Cd and Zn on the molecular mechanism and cell wall of Cosmosbipinnatus is unclear. In this study, a transcriptome was constructed using RNA-sequencing. In C. bipinnatus root transcriptome data, the expression of 996, 2765, and 3023 unigenes were significantly affected by Cd, Zn, and Cd + Zn treatments, respectively, indicating different expression patterns of some metal transporters among the Cd, Zn, and Cd + Zn treatments. With the addition of Zn, the damage to the cell wall was reduced, both the proportion and content of polysaccharides in the cell wall were changed, and Cd accumulation was decreased by 32.34%. In addition, we found that Cd and Zn mainly accumulated in pectins, the content of which increased by 30.79% and 61.4% compared to the CK treatment. Thus, Zn could alleviate the toxicity of Cd to C. bipinnatus. This study revealed the interaction between Cd and Zn at the physiological and molecular levels, broadening our understanding of the mechanisms of tolerance to Cd and Zn stress in cosmos.

FT4-to-FT3 ratio is a novel prognostic marker in subacute combined spinal cord degeneration patients.

Objectives: The FT4-to-FT3 ratio (FFR) variations in patients with subacute combined spinal cord degeneration (SCSD) as a potentially useful prognostic indicator are still unknown. This study aimed to investigate the changes of FFR as a potentially valuable prognostic predictor in patients with SCSD. Methods: This study included 144 consecutive SCSD patients who received standard diagnostic and therapeutic procedures between January 2015 and December 2021 and were admitted to the Department of Neurology at the First Affiliated Hospital of Bengbu Medical University. At the time of admission, we gathered data on all patients' demographics, daily routines, previous chronic conditions, medication histories, and other clinical details. For the purpose of measuring FFR, blood samples were specifically taken within 48 h of admission. The degree of neurological impairment of patients was assessed using the functional disability scale at the time of admission. At 6 months following discharge, the Modified Rankin Scale (mRS) was used to evaluate the clinical prognosis. To evaluate the relationship between the FFR and the risks of a poor outcome (mRS > 2), univariate and multivariate logistic regression analysis was utilized. The significance of the FT4/FT3 ratio in predicting the clinical outcomes in SCSD patients 6 months after discharge was assessed using the area under curve-receiver operating characteristic (AUC-ROC). Results: About 90 patients (62.5%) of the 144 patients had poor outcomes, while 54 (37.5%) had favorable outcomes. Higher FFR at admission was independently linked to higher odds of a poor outcome, according to a logistic analysis. With an optimized cutoff value of >2.843, the FFR exhibited the maximum accuracy for predicting a poor outcome, according to the AUC‒ROC curve (AUC 0.731, P < 0.001; sensitivity, 77.8%; specificity, 83.3%). FFR was identified as an independent predictor of poor outcomes by multivariate logistic regression (OR, 2.244; 95% CI, 1.74-2.90; P < 0.001). Conclusions: We discovered that in patients who had a bad result 6 months after discharge, the FFR had dramatically increased at the time of admission, providing a unique prognostic marker in patients with SCSD.

Methyl jasmonate regulation of pectin polysaccharides in Cosmos bipinnatus roots: A mechanistic insight into alleviating cadmium toxicity.

Methyl jasmonate (MeJA), a crucial phytohormone, which plays an important role in resistance to Cadmium (Cd) stress. The cell wall (CW) of root system is the main location of Cd and plays a key role in resistance to Cd toxicity. However, the mechanism effect of MeJA on the CW composition and Cd accumulation remain unclear. In this study, the contribution of MeJA in regulating CW structure, pectin composition and Cd accumulation was investigated in Cosmos bipinnatus. Phenotypic results affirm MeJA's significant role in reducing Cd-induced toxicity in C. bipinnatus. Notably, MeJA exerts a dual impact, reducing Cd uptake in roots while increasing Cd accumulation in the CW, particularly bound to pectin. The molecular structure of pectin, mainly uronic acid (UA), correlates positively with Cd content, consistent in HC1 and cellulose, emphasizing UA as pivotal for Cd binding. Furthermore, MeJA modulates pectin methylesterase (PME) activity under Cd stress, influencing pectin's molecular structure and homogalacturonan (HG) content affecting Cd-binding capacity. Chelate-soluble pectin (CSP) within soluble pectins accumulates a substantial Cd proportion, with MeJA regulating both UA content and the minor component 3-deoxy-oct-2-ulosonic acid (Kdo) in CSP. The study delves into the intricate regulation of pectin monosaccharide composition under Cd stress, revealing insights into the CW's physical defense and Cd binding. In summary, this research provides novel insights into MeJA-specific mechanisms alleviating Cd toxicity in C. bipinnatus, shedding light on complex interactions between MeJA, and Cd accumulation in CW pectin polysaccharide.

Designing and preparing supramolecular encapsulation systems based on fraxetin and cyclodextrins for highly selective detection of nicotine.

Herein, a series of water-soluble supramolecular inclusion complexes (ICs) probes were prepared using cyclodextrins (CDs) and fraxetin (FRA) to detect nicotine (NT) with high selectivity in vitro and in vivo. The FRA/CD ICs prepared through the saturated solution method exhibited excellent water solubility, stability, and biocompatibility. A clear host-guest inclusion model was provided by the theoretical calculations. The investigation revealed that NT was able to enter into the cavities of FRA/ß-CD IC and FRA/γ-CD IC, and further formed charge transfer complexes with FRA in the CD cavities, resulting in a rapid and highly selective fluorescence-enhanced response with the lowest detection limits of 1.9 × 10-6 M and 9.7 × 10-7 M, and the linear response ranged from 0.02 to 0.3 mM and 0.01-0.05 mM, respectively. The IC probes showed good anti-interference performance to common interferents or different pH environments, with satisfactory reproducibility and repeatability of response to NT. Furthermore, the potentiality of the probes was confirmed through fluorescence imaging experiments using human lung cancer cells and the lung tissue of mice. This study offers a fresh perspective for detecting NT in environmental and biomedical analysis.

Pyrazine-Functionalized Donor-Acceptor Covalent Organic Frameworks for Enhanced Photocatalytic H2 Evolution with High Proton Transport.

The well-defined 2D or 3D structure of covalent organic frameworks (COFs) makes it have great potential in photoelectric conversion and ions conduction fields. Herein, a new donor-accepter (D-A) COF material, named PyPz-COF, constructed from electron donor 4,4',4″,4'″-(pyrene-1,3,6,8-tetrayl)tetraaniline and electron accepter 4,4'-(pyrazine-2,5-diyl)dibenzaldehyde with an ordered and stable π-conjugated structure is reported. Interestingly, the introduction of pyrazine ring endows the PyPz-COF a distinct optical, electrochemical, charge-transfer properties, and also brings plentiful CN groups that enrich the proton by hydrogen bonds to enhance the photocatalysis performance. Thus, PyPz-COF exhibits a significantly improved photocatalytic hydrogen generation performance up to 7542 µmol g-1 h-1 with Pt as cocatalyst, also in clear contrast to that of PyTp-COF without pyrazine introduction (1714 µmol g-1 h-1 ). Moreover, the abundant nitrogen sites of the pyrazine ring and the well-defined 1D nanochannels enable the as-prepared COFs to immobilize H3 PO4 proton carriers in COFs through hydrogen bond confinement. The resulting material has an impressive proton conduction up to 8.10 × 10-2 S cm-1 at 353 K, 98% RH. This work will inspire the design and synthesis of COF-based materials with both efficient photocatalysis and proton conduction performance in the future.

Alternations of interhemispheric functional connectivity in patients with optic neuritis using voxel-mirrored homotopic connectivity: A resting state fMRI study.

BACKGROUND AND PURPOSE: We used the voxel-mirrored homotopic connectivity (VMHC) method to investigate brain interhemispheric functional connectivity changes in patients with optic neuritis (ON). METHODS: A total of 22 ON patients and 22 healthy controls (HCs) closely matched in age, sex, and weight were enrolled. All participants underwent resting-state functional magnetic resonance imaging (rs-fMRI). Functional interaction between the hemispheres was assessed with the VMHC method. Correlation analysis was applied to explore the association between altered VMHC values in different brain areas and cognitive features. Receiver operating characteristic (ROC) curve analysis was applied to distinguish ON patients from HCs. RESULTS: Compared with HCs, ON patients had obviously reduced VMHC values in the right superior temporal gyrus, left margin superior gyrus, right superior motor cortex, and left middle cingulate gyrus. a negative relationship between best-corrected visual acuity and VMHC values in left margin superior gyrus was found, besides, the VMHC values within the right superior motor cortex and the right superior temporal gyrus were also anti-correlated with the Hamilton Depression Scales. The ROC curve displayed high diagnostic values in those altered regions. CONCLUSION: Abnormal VMHC values may reflect the underlying neuropathologic mechanism of ON.

Inverse Association of Fruit and Vegetable Consumption with Nonalcoholic Fatty Liver Disease in Chinese Patients with Type 2 Diabetes Mellitus.

We aimed to investigate the association of fruit and vegetable consumption with nonalcoholic fatty liver disease (NAFLD) in Chinese patients with type 2 diabetes mellitus (T2DM). This cross-sectional study included 2667 Chinese patients with T2DM aged 18 to 76 years from March 2017 to October 2021. Dietary intake was assessed using a food frequency questionnaire, and prevalent NAFLD was diagnosed with abdominal ultrasonography. High fruit−vegetable consumption was determined using ≥500 g/day consumption of both fruit and vegetable, and both fruit and vegetable consumption were divided into three categories of <200 g/day (low), 200−400 g/day (median) and >400 g (high). The primary outcome measurement was multivariate-adjusted odds ratios (ORs) with 95% confidence intervals (CIs) for the prevalence of NAFLD in relation to the highest fruit and (or) vegetable intake compared with the lowest. Secondary analyses were conducted to assess the effects of either fruit or vegetable intake on the fatty liver index (FLI) using multivariable linear regressions. There were 1694 men and 973 women in this study, and 1445 (54.06%) participants had prevalent NAFLD. Patients with high fruit−vegetable intake had a lower prevalence of NAFLD than those with low fruit−vegetable intake (52.04% vs. 56.48%), but this difference was not statistically significant (p = 0.065). Vegetable intake had a significantly inverse association with NAFLD (OR: 0.68, 95% CI: 0.52−0.90), but this association was not pronounced with fruit intake (OR: 1.23, 95% CI: 0.89−1.69) or fruit−vegetable intake (OR: 0.90, 95% CI: 0.73−1.10). Additional analyses showed that an increase in vegetable intake was linearly associated with a significant reduction in FLI (ß: −1.028, 95% CI: −1.836, −0.219). In conclusion, higher vegetable consumption was associated with lower odds of NAFLD in Chinese patients with T2DM, which suggested that increased vegetable intake might protect patients with diabetes against NAFLD.

Myokine myostatin is a novel predictor of one-year radiographic progression in patients with rheumatoid arthritis: A prospective cohort study.

Background: Associations between rheumatoid arthritis (RA) and reduced skeletal muscle have been studied, and we firstly reported myopenia independently predict one-year radiographic progression in RA. Myokine myostatin can negatively regulate skeletal muscle mass and promote osteoclast differentiation. However, there is no report about their relationships in RA patients. We firstly explored the relationship of serum myostatin and disease characteristics, as well as aggravated joint destruction during one-year follow-up. Methods: Consecutive RA patients were recruited from a real-world prospective cohort and completed at least one-year follow-up. Baseline serum level of myostatin was measured by enzyme-linked immunosorbent assay. Clinical data in RA patients as well as muscle index in both RA patients and healthy controls were collected. One-year radiographic progression as primary outcome was defined by a change in the total Sharp/van der Heijde modified score ≥0.5 units. Results: Totally 344 RA patients (age 47.9 ± 12.5 years, 84.0% female) and 118 healthy control subjects (age 42.8 ± 11.3 years, 74.6% female) were recruited. Compared with healthy controls, RA patients showed a higher level of serum myostatin at baseline (3.241 ± 1.679 ng/ml vs. 1.717 ± 0.872 ng/ml, P<0.001), although lower appendicular skeletal muscle mass index (ASMI, 6.0 ± 0.9 kg/m2 vs. 6.5 ± 1.0 kg/m2, P<0.001). In RA patients, those with high myostatin level showed a higher rate of radiographic progression than low myostatin group (45.3% vs. 18.6%, P<0.001). Furtherly, RA patients were stratified into four subgroups according to serum myostatin and myopenia. Compared with other three subgroups, RA patients with high myostatin overlapping myopenia had the highest rate of radiographic progression (67.2% vs. 10.3%-31.4%, P<0.001), as well as the lowest proportion of remission and the highest rate of physical dysfunction during one-year follow-up. After adjustment for confounding factors, high serum myostatin (AOR=3.451, 95%CI: 2.016-5.905) and myopenia (AOR=2.387, 95%CI: 1.416-4.022) at baseline were risk factors for one-year radiographic progression, especially for those with high myostatin overlapping myopenia (AOR=10.425, 95%CI: 3.959-27.450) as the highest-risk individuals among four subgroups. Significant synergistic interaction effect was observed between high myostatin and myopenia on one-year radiographic progression (AP=66.3%, 95%CI: 43.2%-89.3%). Conclusion: Myostatin is a novel predictor of aggravated joint destruction in RA patients which has synergistic interaction with myopenia for predicting value.

Elevated levels of fructosamine are independently associated with SARS-CoV-2 reinfection: A 12-mo follow-up study.

BACKGROUND: The association between blood levels of fructosamine (FMN) and recurrent coronavirus disease 2019 (COVID-19) is currently unclear. AIM: To investigate a prospective relationship between blood levels of FMN and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reinfection. METHODS: A total of 146 Chinese hospitalized patients infected with SARS-CoV-2 were consecutively collectively recruited and followed from January 2020 to May 2021. Diagnosis of COVID-19 and SARS-CoV-2 reinfection was based on the diagnostic criteria and treatment protocol in China. The levels of FMN were determined in blood and divided into tertiles based on their distribution in the cohort of COVID-19 patients. Multivariate-adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated for SARS-CoV-2 reinfection across the tertiles of FMN levels. A Cox regression model was used to generate the HR for SARS-CoV-2 reinfection in the participants in the top tertile of FMN levels compared with those at the bottom. Disease-free survival was used as the time variable, and relapse was used as the state variable, adjusted for age, gender, influencing factors such as diabetes mellitus, hypertension, and corticosteroid therapy, and clinical indexes such as acute liver failure, acute kidney failure, white blood cell (WBC) count, C-reactive protein, prognostic nutritional index (PNI), and blood lipids. Kaplan-Meier analysis with log-rank tests was used to compare the survival rate between patients with elevated FMN levels (FMN > 1.93 mmol/L, the top tertile) and those with nonelevated levels. RESULTS: Clinical data for the 146 patients with confirmed COVID-19 [age 49 (39-55) years; 49% males] were analyzed. Eleven patients had SARS-CoV-2 reinfection. The SARS-CoV-2 reinfection rate in patients with elevated FMN levels was significantly higher than that in patients with nonelevated FMN (17% vs 3%; P = 0.008) at the end of the 12-mo follow-up. After adjustments for gender, age, diabetes mellitus, hypertension, corticosteroid therapy, WBC count, PNI, indexes of liver and renal function, and blood lipids, patients with nonelevated FMN levels had a lower risk of SARS-CoV-2 reinfection than those with elevated FMN levels (HR = 6.249, 95%CI: 1.377-28.351; P = 0.018). Kaplan-Meier analysis showed that the cumulative survival rate of patients infected with SARS-CoV-2 was higher in patients with nonelevated FMN levels than in those with elevated FMN levels (97% vs 83%; log rank P = 0.002). CONCLUSION: Elevated levels of FMN are independently associated with SARS-CoV-2 reinfection, which highlights that patients with elevated FMN should be cautiously monitored after hospital discharge.

Heterogeneous Nitrogen Supply With High Frequency and Ramet Damage Increases the Benefits of Clonal Integration in Invasive Hydrocotyle vulgaris.

Nitrogen (N) deposition significantly affects the growth and the function of invasive clonal plants. However, the effects of heterogeneous N supply with different frequencies on the growth and the potential contribution of clonal integration in invasion plants are still unclear, especially in the complex environment considering ramet damage. To address this question, apical and basal ramets of the clonal invader Hydrocotyle vulgaris were connected or disconnected, N was added to the basal ramets with a high frequency, a low frequency, or no supply, and the total N quantity was the same for the different frequency. Furthermore, 8 aphids were placed on the apical ramets, and 30% of each leaf was cut off to cause damage. The connection between ramets significantly increased the biomass, total carbon (C), and total N of the basal and apical ramets. Higher frequency N supply significantly increased the biomass, total C, and total N of the basal ramets and the entire clonal fragment biomass. The damage had no significant effect on the growth of basal and apical ramets. Especially, under the high N frequency and ramet damage condition, the connection between ramets more significantly increased the biomass, total C, and total N of the apical ramets and the entire clonal fragment biomass. In addition, the uptake rates of 15 NH 4 + and 15 NO 3 - in H. vulgaris had no significant difference, and N supply increased the uptake rates of 15 NH 4 + and 15 NO 3 - of the basal ramets. Our results suggest that both higher frequency N supply and clonal integration are beneficial to the growth of H. vulgaris. Moreover, the heterogeneous N supply with high frequency and ramet damage increases the benefits of clonal integration in H. vulgaris. These findings improve our understanding of the response of clonal invader H. vulgaris to nitrogen deposition and ramet damage.

Effect of a carbohydrate-rich beverage on rate of cesarean delivery in primigravidae with epidural labor analgesia: a multicenter randomized trial.

BACKGROUND: Labor represents a period of significant physical activity. Inefficient energy supply may delay labor process and even lead to cesarean delivery. Herein we investigated whether ingestion of a carbohydrate-rich beverage could reduce cesarean delivery in laboring women with epidural analgesia. METHODS: This multicenter randomized trial was conducted in obstetrician-led maternity units of nine tertiary hospitals in China. Primigravidae with single term cephalic pregnancy who were preparing for vaginal birth under epidural analgesia were randomized to intake a carbohydrate-rich beverage or commercially available low-carbohydrate beverages during labor. The primary outcome was the rate of cesarean delivery. Secondary outcomes included maternal feeling of hunger, assessed with an 11-point scale where 0 indicated no hunger and 10 the most severe hunger, and maternal and neonatal blood glucose after childbirth. RESULTS: Between 17 January 2018 and 20 July 2018, 2008 women were enrolled and randomized, 1953 were included in the intention-to-treat analysis. The rate of cesarean delivery did not differ between the two groups (11.3% [111/982] with carbohydrate-rich beverage vs. 10.9% [106/971] with low-carbohydrate beverages; relative risk 1.04, 95% CI 0.81 to 1.33; p = 0.79). Women in the carbohydrate-rich beverage group had lower subjective hunger score (median 3 [interquartile range 2 to 5] vs. 4 [2 to 6]; median difference - 1; 95% CI - 1 to 0; p < 0.01); their neonates had less hypoglycemia (1.0% [10/968] vs. 2.3% [22/956]; relative risk 0.45; 95% CI 0.21 to 0.94; p = 0.03) when compared with those in the low-carbohydrate beverage group. They also had higher rates of maternal hyperglycemia (6.9% [67/965] vs. 1.9% [18/953]; p < 0.01) and neonatal hyperglycemia (9.2% [89/968] vs. 5.8% [55/956]; p < 0.01), but none required special treatment. CONCLUSIONS: For laboring primigravidae with epidural analgesia, ingestion of a carbohydrate-rich beverage compared with low-carbohydrate beverages did not reduce cesarean delivery, but relieved maternal hunger and reduced neonatal hypoglycemia at the expense of increased hyperglycemia of both mothers and neonates. Optimal rate of carbohydrate supplementation remains to be determined. TRIAL REGISTRATION: www.chictr.org.cn ; identifier: ChiCTR-IOR-17011994 ; registered on 14 July 2017.

A Matrix Prediction Model for the 6-Month Mortality Risk in Patients With Anti-Melanoma Differentiation-Associated Protein-5-Positive Dermatomyositis.

Objectives: The purpose of this study was to investigate the baseline independent risk factors for predicting 6-month mortality of patients with anti-melanoma differentiation-associated gene 5 (anti-MDA5)-positive dermatomyositis (DM) and develop a matrix prediction model formed by these risk factors. Methods: The hospitalized patients with DM who completed at least 6-month follow-up were recruited as a derivation cohort. The primary exposure was defined as positive anti-MDA5 at the baseline. The primary outcome was all-cause 6-month mortality after enrollment. A matrix prediction model was developed in the derivation cohort, and another published cohort was used for external validation. Results: In derivation cohort, 82 patients with DM were enrolled (mean age of onset 50 ± 11 years and 63% women), with 40 (49%) showing positive anti-MDA5. Gottron sign/papules (OR: 5.135, 95%CI: 1.489-17.708), arthritis (OR: 5.184, 95%CI: 1.455-18.467), interstitial lung disease (OR: 7.034, 95%CI: 1.157-42.785), and higher level of C4 (OR: 1.010, 95%CI: 1.002-1.017) were the independent associators with positive anti-MDA5 in patients with DM. Patients with anti-MDA5-positive DM had significant higher 6-month all-cause mortality than those with anti-MDA5-negative (30 vs. 0%). Among the patients with anti-MDA5-positive DM, compared to the survivors, non-survivors had significantly advanced age of onset (59 ± 6 years vs. 46 ± 9 years), higher rates of fever (75 vs. 18%), positive carcinoma embryonic antigen (CEA, 75 vs. 14%), higher level of ferritin (median 2,858 ug/L vs. 619 ug/L, all p < 0.05). A stepwise multivariate Cox regression showed that ferritin ≥1,250 µg/L (HR: 10.4, 95%CI: 1.8-59.9), fever (HR: 11.2, 95%CI: 2.5-49.9), and positive CEA (HR: 5.2, 95%CI: 1.0-25.7) were the independent risk factors of 6-month mortality. A matrix prediction model was built to stratify patients with anti-MDA5-positive DM into different subgroups with various probabilities of 6-month mortality risk. In an external validation cohort, the observed 6-month all-cause mortality was 78% in high-risk group, 43% in moderate-risk group, and 25% in low-risk group, which shows good accuracy of the model. Conclusion: Baseline characteristics such as fever, ferritin ≥1,250 µg/L, and positive CEA are the independent risk factors for 6-month all-cause mortality in patients with anti-MDA5-positive DM. A novel matrix prediction model composed of these three clinical indicators is first proposed to provide a chance for the exploration of individual treatment strategies in anti-MDA5-positive DM subgroups with various probabilities of mortality risk.

Aaptamine derivatives with CDK2 inhibitory activities from the South China Sea sponge Aaptos suberitoides.

Three new aaptamines (1-3) together with two known derivatives (4-5) were isolated from the South China Sea sponge Aaptos suberitoides. The structures of all compounds were unambiguously elucidated by spectroscopic analyses as well as the comparison with literature data. All the compounds were evaluated for their cytotoxic activities against five human cancer cell lines including H1299, H520, SCG7901, CNE-2 and SW680 cells. As a result, compounds 3-5 showed moderate cytotoxicities against H1299 and H520 cells with IC50 values ranging from 12.9 to 20.6 µg/mL. Besides, compounds 3-5 also showed potent inhibitory activities toward cyclin-dependent kinase-2 (CDK2) with IC50 values of 14.3, 3.0 and 6.0 µg/mL, respectively. In addition, compounds 3-5 significantly induced G1 arrests of H1299 cells at low concentrations. Drug affinity responsive target stability (DARTS) experiments were carried out and further demonstrated that compound 3 could effectively bind with CDK2 protein and protect it from the degradation by pronase.

Neck-to-height ratio is positively associated with diabetic kidney disease in Chinese patients with type 2 diabetes mellitus.

Introduction: The aim of this study was to investigate the associations of neck circumference (NC) and neck-to-height (NHR) with diabetic kidney disease (DKD) in Chinese patients with type 2 diabetes mellitus (T2DM). Materials and methods: A total of 2,615 patients with prevalent T2DM were enrolled. NHR was calculated through NC (cm) divided by height (cm), and prevalent DKD was defined as the urinary albumin-to-creatinine ratio (UACR) ≥ 30 mg/g or the estimated glomerular filtration rate (eGFR) < 60 ml/min per 1.73 m2 in the absence of other primary kidney diseases. Results: The levels of NC and NHR were higher in DKD patients compared with non-DKD patients (38.22 vs. 37.71, P = 0.003; 0.232 vs. 0.227, P < 0.001, respectively). After full adjustments, individuals at the highest tertile of NHR had higher odds of DKD than those at the lowest tertile (multivariate-adjusted OR = 1.63, 95% CI: 1.22, 2.18), but this association was not pronounced with NC (multivariate-adjusted OR = 1.24, 95% CI: 0.87, 1.76). Individuals at the highest tertile of NHR had lower eGFR (ß = -4.64, 95% CI: -6.55, -2.74) and higher UACR levels (ß = 0.27, 95% CI: 0.10, 0.45) than those at the lowest tertile. The adverse association between NHR and prevalent DKD remained statistically significant among most of the subgroups analyzed and no interaction effects were observed. Conclusion: The increase in NHR was adversely and independently associated with DKD in this Chinese T2DM population.

Progressive liver injury and increased mortality risk in COVID-19 patients: A retrospective cohort study in China.

BACKGROUND: Liver injury is common and also can be fatal, particularly in severe or critical patients with coronavirus disease 2019 (COVID-19). AIM: To conduct an in-depth investigation into the risk factors for liver injury and into the effective measures to prevent subsequent mortality risk. METHODS: A retrospective cohort study was performed on 440 consecutive patients with relatively severe COVID-19 between January 28 and March 9, 2020 at Tongji Hospital, Wuhan, China. Data on clinical features, laboratory parameters, medications, and prognosis were collected. RESULTS: COVID-19-associated liver injury more frequently occurred in patients aged ≥ 65 years, female patients, or those with other comorbidities, decreased lymphocyte count, or elevated D-dimer or serum ferritin (P < 0.05). The disease severity of COVID-19 was an independent risk factor for liver injury (severe patients: Odds ratio [OR] = 2.86, 95% confidence interval [CI]: 1.78-4.59; critical patients: OR = 13.44, 95%CI: 7.21-25.97). The elevated levels of on-admission aspartate aminotransferase and total bilirubin indicated an increased mortality risk (P < 0.001). Using intravenous nutrition or antibiotics increased the risk of COVID-19-associated liver injury. Hepatoprotective drugs tended to be of assistance to treat the liver injury and improve the prognosis of patients with COVID-19-associated liver injury. CONCLUSION: More intensive monitoring of aspartate aminotransferase or total bilirubin is recommended for COVID-19 patients, especially patients aged ≥ 65 years, female patients, or those with other comorbidities. Drug hepatotoxicity of antibiotics and intravenous nutrition should be alert for COVID-19 patients.

Scutellariabarbata D. Don extraction selectively targets stemness-prone NSCLC cells by attenuating SOX2/SMO/GLI1 network loop.

ETHNOPHARMACOLOGICAL RELEVANCE: Scutellariabarbata D. Don extraction (SBE), a traditional Chinese medicine, has been proved effective against various malignant disorders in clinics with tolerable side-effects when administered alone or in combination with conventional chemotherapeutic regimens. AIM OF THIS STUDY: Multi-drug resistance of cancer is attributed to existence of cancer stemness-prone cells that harbor aberrantly high activation of Sonic Hedgehog (SHH) cascade. Our previous study has demonstrated that SBE sensitized non-small cell lung cancer (NSCLC) cells to Cisplatin (DDP) treatment by downregulating SHH pathway. Yet, whether SBE could prohibit proliferation of cancer stemness-prone cells and its underlying molecular mechanisms remain to be investigated. In this article, we further investigated intervention of SBE on NSCLC cell stemness-associated phenotypes and its potential mode of action. MATERIALS AND METHODS: CCK-8 and clonal formation detection were used to measure the anti-proliferative potency of SBE against NSCLC and normal epithelial cells. Sphere formation assay and RQ-PCR were used to detect proliferation of cancer stemness cells and associated marker expression upon SBE incubation. Mechanistically, DARTS-WB and SPR were used to unveil binding target of SBE. Immunodeficient mice were implanted with patient derived tumor bulk for in vivo validation of anti-cancer effect of SBE. RESULTS: SBE selectively attenuated proliferation and stemness-like phenotypes of NSCLC cells rather than bronchial normal epithelial cells. Drug-protein interaction analysis revealed that SBE could directly bind with stem cell-specific transcription factor sex determining region Y-box 2 (SOX2) and interfere with the SOX2/SMO/GLI1 positive loop. In vivo assay using patient-derived xenografts (PDXs) model further proved that SBE diminished tumor growth and SOX2 expression in vivo. CONCLUSION: Our data indicate that SBE represses stemness-related features of NSCLC cells via targeting SOX2 and may serve as an alternative therapeutic option for clinic treatment.

Nestin+/CD31+ cells in the hypoxic perivascular niche regulate glioblastoma chemoresistance by upregulating JAG1 and DLL4.

BACKGROUND: Failure of glioblastoma (GBM) therapy is often ascribed to different types of glioblastoma stem-like cell (GSLC) niche; in particular, a hypoxic perivascular niche (HPVN) is involved in GBM progression. However, the cells responsible for HPVNs remain unclear. METHODS: Immunostaining was performed to determine the cells involved in HPVNs. A hypoxic chamber and 3-dimensional (3D) microfluidic chips were designed to simulate a HPVN based on the pathological features of GBM. The phenotype of GSLCs was evaluated by fluorescence scanning in real time and proliferation and apoptotic assays. The expression of JAG1, DLL4, and Hes1 was determined by immunostaining, ELISA, Western blotting, and quantitative PCR. Their clinical prognostic significance in GBM HPVNs and total tumor tissues were verified by clinical data and The Cancer Genome Atlas databases. RESULTS: Nestin+/CD31+ cells and pericytes constitute the major part of microvessels in the HPVN, and the high ratio of nestin+/CD31+ cells rather than pericytes are responsible for the poor prognosis of GBM. A more real HPVN was simulated by a hypoxic coculture system in vitro, which consisted of 3D microfluidic chips and a hypoxic chamber. Nestin+/CD31+ cells in the HPVN were derived from GSLC transdifferentiation and promoted GSLC chemoresistance by providing more JAG1 and DLL4 to induce downstream Hes1 overexpression. Poor GBM prognosis correlated with Hes1 expression of tumor cells in the GBM HPVN, and not with total Hes1 expression in GBM tissues. CONCLUSIONS: These results highlight the critical role of nestin+/CD31+ cells in HPVNs that acts in GBM chemoresistance and reveal the distinctive prognostic value of these molecular markers in HPVNs.