Cancer-secreted exosomal miRNAs are emerging mediators of cancer-stromal cross-talk in the tumor environment. Our previous miRNAs array of cervical squamous cell carcinoma (CSCC) clinical specimens ...identified upregulation of miR-221-3p. Here, we show that miR-221-3p is closely correlated with peritumoral lymphangiogenesis and lymph node (LN) metastasis in CSCC. More importantly, miR-221-3p is characteristically enriched in and transferred by CSCC-secreted exosomes into human lymphatic endothelial cells (HLECs) to promote HLECs migration and tube formation in vitro, and facilitate lymphangiogenesis and LN metastasis in vivo according to both gain-of-function and loss-of-function experiments. Furthermore, we identify vasohibin-1 (VASH1) as a novel direct target of miR-221-3p through bioinformatic target prediction and luciferase reporter assay. Re-expression and knockdown of VASH1 could respectively rescue and simulate the effects induced by exosomal miR-221-3p. Importantly, the miR-221-3p-VASH1 axis activates the ERK/AKT pathway in HLECs independent of VEGF-C. Finally, circulating exosomal miR-221-3p levels also have biological function in promoting HLECs sprouting in vitro and are closely associated with tumor miR-221-3p expression, lymphatic VASH1 expression, lymphangiogenesis, and LN metastasis in CSCC patients. In conclusion, CSCC-secreted exosomal miR-221-3p transfers into HLECs to promote lymphangiogenesis and lymphatic metastasis via downregulation of VASH1 and may represent a novel diagnostic biomarker and therapeutic target for metastatic CSCC patients in early stages.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Levosimendan and dobutamine are extensively used to treat sepsis-associated cardiovascular failure in ICU. Nevertheless, the role and mechanism of levosimendan in patients with sepsis-induced ...cardiomyopathy remains unclear. Moreover, previous studies on whether levosimendan is superior to dobutamine are still controversial. More importantly, these studies did not take changes (before-after comparison to the baseline) in quantitative parameters such as ejection fraction into account with the baseline level. Here, we aimed to determine the pros and cons of the two medicines by assessing the changes in cardiac function and blood lactate, mortality, with the standardized mean difference used as a summary statistic. Relevant studies were obtained by a thorough and disciplined literature search in several notable academic databases, including Google Scholar, PubMed, Cochrane Library and Embase until November 2020. Outcomes included changes in cardiac function, lactic acid, mortality and length of hospital stay. A total of 6 randomized controlled trials were included in this study, including 192 patients. Compared with dobutamine, patients treated with levosimendan had a greater improvement of cardiac index (ΔCI) (random effects, SMD = 0.90 0.20,1.60; I
= 76%, P < 0.01) and left ventricular stroke work index (ΔLVSWI) (random effects, SMD = 1.56 0.90,2.21; I
= 65%, P = 0.04), a significant decrease of blood lactate (Δblood lactate) (random effects, MD = - 0.79 - 1.33, - 0.25; I
= 68%, P < 0.01) at 24-h after drug intervention, respectively. There was no significant difference between levosimendan and dobutamine on all-cause mortality in ICU (fixed effect, OR = 0.72 0.39,1.33; I
= 0%, P = 0.99). We combine effect sizes related to different measurement parameters to evaluate cardiac function, which implied that septic patients with myocardial dysfunction might have a better improvement of cardiac function by levosimendan than dobutamine (random effects, SMD = 1.05 0.69,1.41; I
= 67%, P < 0.01). This study suggested a significant improvement of CI, LVSWI, and decrease of blood lactate in septic patients with myocardial dysfunction in ICU after 24-h administration of levosimendan than dobutamine. However, the administration of levosimendan has neither an impact on mortality nor LVEF. Septic patients with myocardial dysfunction may partly benefit from levosimendan than dobutamine, mainly embodied in cardiac function improvement.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Mu-opioid receptors (MORs) are crucial for analgesia by both exogenous and endogenous opioids. However, the distinct mechanisms underlying these two types of opioid analgesia remain largely unknown. ...Here, we demonstrate that analgesic effects of exogenous and endogenous opioids on inflammatory pain are mediated by MORs expressed in distinct subpopulations of neurons in mice. We found that the exogenous opioid-induced analgesia of inflammatory pain is mediated by MORs in Vglut2
glutamatergic but not GABAergic neurons. In contrast, analgesia by endogenous opioids is mediated by MORs in GABAergic rather than Vglut2
glutamatergic neurons. Furthermore, MORs expressed at the spinal level is mainly involved in the analgesic effect of morphine in acute pain, but not in endogenous opioid analgesia during chronic inflammatory pain. Thus, our study revealed distinct mechanisms underlying analgesia by exogenous and endogenous opioids, and laid the foundation for further dissecting the circuit mechanism underlying opioid analgesia.
In conjunction with the classical functions of regulating intestinal, bone, and kidney calcium and phosphorus absorption, as well as bone mineralization of vitamin D, the population-based association ...between low vitamin D status and increased cancer risk is now generally accepted. Inflammation is causally related to oncogenesis. It is widely thought that vitamin D plays an important role in the modulation of the inflammation system by regulating the production of inflammatory cytokines and immune cells, which are crucial for the pathogenesis of many immune-related diseases. Mechanistic studies have shown that vitamin D influences inflammatory processes involved in cancer progression, including cytokines, prostaglandins, MAP kinase phosphatase 5 (MKP5), the nuclear factor kappa B (NF-κB) pathway, and immune cells. Multiple studies have shown that vitamin D has the potential to inhibit tumor development by interfering with the inflammation system. The present review summarizes recent studies of the mechanisms of vitamin D on regulating the inflammation system, which contributes to its potential for cancer prevention and therapy. This review helps answer whether inflammation mediates a causal relationship between vitamin D and tumorigenesis.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
A severe dust storm event originated from the Gobi Desert in Central and East
Asia during 2–7 May 2017. Based on Moderate Resolution Imaging
Spectroradiometer (MODIS) satellite products, hourly ...environmental monitoring
measurements from Chinese cities and East Asian meteorological observation
stations, and numerical simulations, we analysed the spatial and temporal
characteristics of this dust event as well as its associated impact on the
Asia-Pacific region. The maximum observed hourly PM10 (particulate
matter with an aerodynamic diameter ≤ 10 µm) concentration
was above 1000 µg m−3 in Beijing, Tianjin, Shijiazhuang,
Baoding, and Langfang and above 2000 µg m−3 in Erdos, Hohhot,
Baotou, and Alxa in northern China. This dust event affected over
8.35 million km2, or 87 % of the Chinese mainland, and significantly deteriorated air quality in 316 cities of
the 367 cities examined across China. The maximum surface wind speed during
the dust storm was 23–24 m s−1 in the Mongolian Gobi Desert and
20–22 m s−1 in central Inner Mongolia, indicating the potential
source regions of this dust event. Lidar-derived vertical dust profiles in
Beijing, Seoul, and Tokyo indicated dust aerosols were uplifted to an
altitude of 1.5–3.5 km, whereas simulations by the Weather Research and
Forecasting with Chemistry (WRF-Chem) model indicated 20.4 and 5.3 Tg of
aeolian dust being deposited respectively across continental Asia and the
North Pacific Ocean. According to forward trajectory analysis by the FLEXible
PARTicle dispersion (FLEXPART) model, the East Asian dust plume moved across
the North Pacific within a week. Dust concentrations decreased from the East
Asian continent across the Pacific Ocean from a magnitude of 103 to
10−5 µg m−3, while dust deposition intensity ranged from
104 to 10−1 mg m−2. This dust event was unusual due to its
impact on continental China, the Korean Peninsula, Japan, and the North
Pacific Ocean. Asian dust storms such as those observed in early May 2017 may
lead to wider climate forcing on a global scale.
It is still very urgent and challenging to simultaneously develop high‐rate and long‐cycle oxide cathodes for sodium‐ion batteries (SIBs) because of the sluggish kinetics and complex multiphase ...evolution during cycling. Here, the concept of accurately manipulating structural evolution and formulating high‐performance heterostructured biphasic layered oxide cathodes by local chemistry and orbital hybridization modulation is reported. The P2‐structure stoichiometric composition of the cathode material shows a layered P2‐ and O3‐type heterostructure that is explicitly evidenced by various macroscale and atomic‐scale techniques. Surprisingly, the heterostructured cathode displays excellent rate performance, remarkable cycling stability (capacity retention of 82.16% after 600 cycles at 2 C), and outstanding compatibility with hard carbon anode because of the integrated advantages of intergrowth structure and local environment regulation. Meanwhile, the formation process from precursors during calcination and the highly reversible dynamic structural evolution during the Na+ intercalation/deintercalation process are clearly articulated by a series of in situ characterization techniques. Also, the intrinsic structural properties and corresponding electrochemical behavior are further elucidated by the density of states and electron localization function of density functional theory calculations. Overall, this strategy, which finely tunes the local chemistry and orbitals hybridization for high‐performance SIBs, will open up a new field for other materials.
An abnormal heterostructured biphasic layered oxide cathode for sodium‐ion batteries (SIBs) is successfully constructed, and its dynamic formation process, intrinsic structural properties, and electrochemical behavior are elucidated by a series of in situ characterization techniques and density functional theory calculations. The concept of accurately manipulating structural evolution and formulating heterostructured cathode materials by local chemistry and orbital hybridization modulation is further demonstrated.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Immunoglobulin G4-related sialadenitis (IgG4-RS) is a newly recognized immune-mediated systemic disease. Despite its good response to steroid therapy, its treatment protocol is not standardized and ...the long-term outcome is controversial. The study was conducted to determine the short-term and long-term outcomes of IgG4-RS patients treated with glucocorticoids and steroid-sparing immunosuppressive agents, to analyze secretory function, serological and radiological changes in salivary glands and to assess the usefulness of serum IgG4 level as an indicator of disease activity.
IgG4-RS patients who were treated for more than 3 months were enrolled. Serological tests, salivary gland function assessment and computed tomography (CT) were performed before treatment and during follow up. The treatment outcomes in the short and the long term were evaluated, and the relationship between serum IgG4 level and salivary gland volume was analyzed.
Glucocorticoids were used in all 43 patients and steroid-sparing immunosuppressive agents in 38 patients (88.4%). The follow-up period was 24.6 ± 14.9 months. Clinical remission was achieved in all patients after induction therapy. During short-term observation, salivary gland secretion significantly increased, and the serum IgG4 levels, the volumes and CT values of submandibular and parotid gland decreased significantly (P < 0.001). For long term, relapse occurred in 32.5% patients within 55 months in the regularly treated group, while all seven irregularly treated patients relapsed. However, the relapse-free survival curves were not significantly different between the steroid monotherapy and the combination therapy groups (P = 0.566). Submandibular glands, lacrimal glands, sublingual glands, nasal and paranasal cavity were commonly relapsing organs. In clinically stable patients, a serologically unstable condition occurred in 54.9% patients within 55 months and medication adjustment was performed accordingly. Volume changes in the submandibular and parotid glands were associated with serum IgG4 levels and time of follow up (R
= 0.905, P < 0.0001 and R
= 0.9334, P < 0.0001, respectively).
The combination of glucocorticoid and steroid-sparing agents could be effective for treating IgG4-RS, and restoring salivary gland function. Serum IgG4 levels could predict disease activity.
The ongoing coronavirus disease 2019 (COVID-19) pandemic has prioritized the development of small-animal models for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We adapted a clinical ...isolate of SARS-CoV-2 by serial passaging in the respiratory tract of aged BALB/c mice. The resulting mouse-adapted strain at passage 6 (called MASCp6) showed increased infectivity in mouse lung and led to interstitial pneumonia and inflammatory responses in both young and aged mice after intranasal inoculation. Deep sequencing revealed a panel of adaptive mutations potentially associated with the increased virulence. In particular, the N501Y mutation is located at the receptor binding domain (RBD) of the spike protein. The protective efficacy of a recombinant RBD vaccine candidate was validated by using this model. Thus, this mouse-adapted strain and associated challenge model should be of value in evaluating vaccines and antivirals against SARS-CoV-2.
ABSTRACT
Background
This study aimed to investigate the effect of systemic inflammation, assessed by high sensitivity C‐reactive protein (hs‐CRP) levels, on prediabetes progression and regression in ...middle‐aged and older adults based on the China Health and Retirement Longitudinal Study (CHARLS).
Methods
Participants with prediabetes from CHARLS were followed up 4 years later with blood samples collected for measuring fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c). The level of hs‐CRP was assessed at baseline and categorized into tertiles (low, middle, and high groups). Prediabetes at baseline and follow‐up was defined primarily according to the American Diabetes Association (ADA) criteria. Logistic regression models were used to estimate the odds ratios (ORs) and confidence intervals (CIs). We also performed stratified analyses according to age, gender, BMI, the presence of hypertension, and the disease history of heart disease and dyslipidemia and sensitivity analyses excluding a subset of participants with incomplete data.
Results
Of the 2,874 prediabetes included at baseline, 834 participants remained as having prediabetes, 146 progressed to diabetes, and 1,894 regressed to normoglycemia based on ADA criteria with a 4 year follow‐up. After multivariate logistics regression analysis, prediabetes with middle (0.67–1.62 mg/L) and high (>1.62 mg/L) hs‐CRP levels had an increased incidence of progressing to diabetes compared with prediabetes with low hs‐CRP levels (<0.67 mg/L; OR = 1.846, 95%CI: 1.129–3.018; and OR = 1.632, 95%CI: 0.985–2.703, respectively), and the incidence of regressing to normoglycemia decreased (OR = 0.793, 95%CI: 0.645–0.975; and OR = 0.769, 95%CI: 0.623–0.978, respectively). Stratified analyses and sensitivity analyses showed consistent results.
Conclusions
Low levels of hs‐CRP are associated with a high incidence of regression from prediabetes to normoglycemia and reduced odds of progression to diabetes.
This study found that low levels of hs‐CRP are associated with a high incidence of regression from prediabetes to normoglycemia and reduced odds of progression to diabetes. Subgroup analyses showed a stronger association between hs‐CRP and type 2 diabetes in women than in men. Thus, prediabetes may need to be closely monitored in middle‐aged and older women with elevated hs‐CRP. In addition, whether a lower cutoff value for hs‐CRP elevation in women should be proposed is a question worthy of future research.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Layered transition metal oxide (NaxTMO2), being one of the most promising cathode candidates for sodium‐ion batteries (SIBs), have attracted intensive interest because of their nontoxicity, high ...theoretical capacities, and easy manufacturability. However, their physical and electrochemical properties of water sensitivity, sluggish Na+ transport kinetics, and irreversible multiple‐phase translations hinder the practical application. Here, a concept of surface lattice‐matched engineering is proposed based on in situ spinel interfacial reconstruction to design a spinel coating P2/P3 heterostructure cathode material with enhanced air stability, rate, and cycle performance. The novel structure and its formation process are verified by transmission electron microscopy and in situ high‐temperature X‐ray diffraction. The electrode exhibits an excellent rate performance with the highly reversible phase transformation demonstrated by in situ charging/discharging X‐ray diffraction. Additionally, even after a rigorous water sensitivity test, the electrode materials still retain almost the same superior electrochemical performance as the fresh sample. The results show that the surface spinel phase can play a vital role in preventing the ingress of water molecules, improving transport kinetics, and enhancing structural integrity for NaxTMO2 cathodes. The concept of surface lattice‐matched engineering based on in situ spinel interfacial reconstruction will be helpful for designing new ultra‐stable cathode materials for high‐performance SIBs.
The formation process and function mechanism for inhibiting phase transformation and enhancing air stability of surface lattice‐matched engineering based on in situ spinel interfacial reconstruction are studied. This strategy of designing heterostructure with in situ interfacial reconstruction will inspire the exploitation of new chemistries and materials.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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